Benzofuran derivatives and their use as antibacterial agents

ABSTRACT

The invention relates to novel benzofuran derivatives and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as anti-infectives.

[0001] The present invention relates to novel2,4-diamino-5-(substituted) pyrimidines, to pharmaceutical compositionscontaining them, to processes for preparing them and their compositions,to intermediates for making them and to their use in the treatment ofmicrobial infections.

[0002] Certain 2,4-diamino-5-benzylpyrimidines have been demonstrated tobe potent inhibitors of dihydrofolate reductase (DHFR), which catalysesthe reduction of dihydrofolic acid to tetrahydrofolic acid (THFA). Thisproperty has been shown to result frequently in useful pharmaceuticalproperties particularly in the treatment of bacterial infections. Thus,U.K. Patent Specification No. 875,562 discloses inter alia2,4-diamino-5-benzylpyrimidines wherein the benzyl moiety is substitutedby three C₁₋₄ alkoxy groups.

[0003] Trimethoprim, 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine,is specifically disclosed in U.K. Patent No. 875, 562 and is the mostactive general antibacterial agent amongst the2,4-diamino-5-benzylpyrimidines known to date. Due to their mode ofaction, these benzylpyrimidines potentiate the antibacterial activity ofthe sulphonamides, and Trimethoprim has been used extensively over thelast decade in human therapy in combination with various sulphonamides,and in particular with sulphamethoxazole, for the treatment of bacterialinfections.

[0004] European Patent Applications Nos. 81109631.2 and 83104240.3disclose inter alia also such type of compounds and their use.

[0005] It has now been found that a group of novel benzofuranderivatives is more potent than e.g. Trimethoprim and is especiallyactive against Gram positive pathogens like Staphylococcus aureus,Staphylococcus epidermidis, Enterococcus faecalis or Streptococcuspneumoniae and at the same time also against Gram negative pathogenslike Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae orProteus vulgaris. The compounds proved to be especially potent againstrespiratory tract pathogens.

[0006] Therefore, the present invention relates to novel compounds ofthe general formula I

[0007] wherein

[0008] R¹ represents straight or branched chain lower alkyl with 2 to 6carbon atoms; cycloalkylmethyl with 3 to 6 carbon atoms; aryl;arylmethyl or heteroarymethyl, the aryl and heteroaryl group may bemono-, di- or tri-substituted with halogen, amino, hydroxy, nitro,trifluoromethyl, lower alkyloxy, lower alkylcarbonylamino,arylcarbonylamino, whereby these substituents may be the same ordifferent; straight or branched chain lower alkylcarbonyl with up to 6carbon atoms; cycloalkylcarbonyl with 3 to 6 carbon atoms;cycloalkylhydroxymethyl with 3 to 6 carbon atoms; arylcarbonyl, the arylgroup may be mono-, di or tri-substituted with halogen, amino, loweralkyloxy, lower alkylcarbonylamino, arylcarbonylamino, whereby thesesubstituents may be the same or different; arylhydroxymethyl, the arylgroup may be mono-, di- or tri-substituted with halogen, amino, loweralkyloxy, lower alkylcarbonylamino, arylcarbonylamino, whereby thesesubstituents may be the same or different; straight or branched chainlower alkenyl with 2 to 6 carbon atoms; hydroxy-lower alkyl with 1 to 6carbon atoms; fluoro-lower alkyl with 1 to 6 carbon atoms; aryloxy-loweralkyl whereby the aryl group may be mono-, di- or tri-substituted withhalogen, amino, lower alkyloxy, lower alkylcarbonylamino,arylcarbonylamino, whereby these substituents may be the same ordifferent; arylthio-lower alkyl whereby the aryl group may be mono-, di-or tri-substituted with halogen, amino, lower alkyloxy, loweralkylcarbonylamino, arylcarbonylamino, whereby these substituents may bethe same or different; arylamino-lower alkyl whereby the aryl group maybe mono-, di- or tri-substituted with halogen, amino, lower alkyloxy,lower alkylcarbonylamino, arylcarbonylamino, whereby these substituentsmay be the same or different; lower alkenyloxy lower alkyl whereby thelower alkenyl group may contain 2 to 4 carbon atoms and the lower alkylgroup may contain 1 or 2 carbon atoms; benzyloxy lower alkyl whereby thebenzyl group may be mono-, di- or tri-substituted with halogen, amino,lower alkyloxy, lower alkylcarbonylamino, arylcarbonylamino, wherebythese substituents may be the same or different; lower alkylamino loweralkyl whereby the lower alkyl groups may contain 1 to 3 carbon atoms;heterocyclylmethyl containing one to three hetero atoms which can be thesame or different and which may be substituted with lower alkyl,halogen, amino, lower alkyloxy, hydroxy, lower alkylcarbonylamino,arylcarbonylamino and benzofused derivatives thereof.

[0009] R² and R³ independently represent hydrogen; lower alkyl with 1 to3 carbon atoms; or together a lower alkylene group with 1 to 3 carbonatoms bridging the oxygen atoms and forming a five, six or sevenmembered ring;

[0010] R⁴ represents hydrogen; straight or branched chain lower alkylwith 1 to 4 carbon atoms;

[0011] and pharmaceutically acceptable salts and N-oxides thereof.

[0012] In the definitions of the general formula I—if not otherwisestated—the expression lower means straight and branched chain groupswith either one or two to six or three carbon atoms, preferably 1 to 3carbon atoms. Examples of lower alkyl and lower alkoxy groups aremethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl,tert.-butyl, pentyl, hexyl, trifluoromethyl, chloromethyl, fluoromethyl,hydroxymethyl, carbahdehyd, thiomethyl, methoxy, ethoxy, propoxy,butoxy, iso-butoxy, sec.-butoxy and tert.-butoxy. Lower alkylene groupsas bridging two oxygen atoms are preferably methylen(-dioxy),ethylen(-dioxy) and propylen(-dioxy) groups and forming in this way afive-, six- or seven-membered ring. Examples of lower alkanoyl-groupsare acetyl, propanoyl and butanoyl. Lower alkenylen means e.g.vinylen,propenylen and butenylen. Lower alkenyl and lower alkynyl means groupslike ethylen, propylen, butylen, 2-methyl-propenyl, and ethinylen,propinylen, butinylen, pentinylen, 2-methyl-pentinylen etc. Loweralkenyloxy means allyloxy, vinyloxy, propenyloxy and the like.

[0013] The expression cycloalkyl means a saturated cyclic hydrocarbonring with 3 to 6 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl, which may be substituted with lower alkyl, hydroxy-loweralkyl, amino-lower alkyl, lower alkoxy-lower alkyl and lower alkenylengroups. The expression heteroaryl means six-membered aromatic ringscontaining one to four nitrogen atoms, benzofused six-membered aromaticrings containing one to three nitrogen atoms, five-membered aromaticrings containing one oxygen or one nitrogen or one sulfur atom, benzo-fused five-membered aromatic rings containing one oxygen or one nitrogenor one sulfur atom, five membered aromatic rings containig an oxygen andnitrogen atom and benzo fused derivatives thereof, five-memberedaromatic rings containing a sulfur and a nitrogen atom and benzo fusedderivatives thereof, five-membered aromatic rings containing twonitrogen atoms and benzo fused derivatives thereof, five memberedaromatic rings containing three nitrogen atoms and benzo fusedderivatives thereof or the tetrazolyl ring e.g. furanyl, thienyl,pyrrolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl,triazinyl, thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, oxazolyl,isoxazolyl, etc. whereby such rings may be substituted with lower alkyl,lower alkenyl, amino, amino-lower alkyl, halogen, hydroxy, lower alkoxy,trifluoromethoxy or trifluoromethyl. The expression aryl representsunsubstituted as well as mono-, di- or tri-substituted aromatic ringswith 6 to 10 carbon atoms like phenyl or naphthyl rings which may besubstituted with aryl, halogen, hydroxy, lower alkyl, lower alkenyl,lower alkynyl, lower alkoxy, lower alkenyloxy, lower alkynyl-loweralkyl-oxy, lower alkenylen, lower alkylenoxy or lower alkylendioxyforming with the phenyl ring a five- or six-membered ring, hydroxy-loweralkyl, hydroxy-lower alkenyl, hydroxy-lower alkyl-lower alkynyl, loweralkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy, trifluoromethyl,trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl, heterocyclyl,heteroaryl. The expression heterocyclyl represents saturated andunsaturated, but not aromatic, three- to six-membered rings containingone to three nitrogen, oxygen or sulfur atoms which may be the same ordifferent like azyridinyl, piperidinyl, mopholinyl, piperazinyl,tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl,tetrahydrofuranyl, dihydroimidazolyl, dihydropyrazoyl, pyrazolidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinilinyl,dihydroisoquinolinyl.

[0014] Preferred compounds are compounds of formula I, wherein R¹ isstraight or branched chain lower alkyl with 2 to 6 carbon atoms;cycloalkylmethyl with 3 to 6 carbon atoms; aryl; arylmethyl orheteroarymethyl, the aryl and heteroaryl group may be mono- or disubstituted with halogen, amino, hydroxy, nitro, trifluoromethyl, loweralkyloxy, lower alkylcarbonylamino, arylcarbonylamino, whereby thesesubstituents may be the same or differen, and R² and R³ are methyl ortogether are a methylen group bridging the oxygen atoms to which theyare attached and R⁴ is hydrogen or methyl.

[0015] Especially preferred compounds are compounds of formula I,wherein R¹ is 4-methoxy-benzyl, phenyl, benzyl, cyclopropylmethyl,4-fluoro-benzyl, 3,4-dihydro-1H-isoquinolin-2-ylmethyl,4-methoxy-benzyloxymethyl, 4-acetylaminophenyl-sulfanyl-methyl,4-trifluoromethyl-phenoxymethyl, 4-amino-phenoxymethyl, allyloxymethyl,phenyl-[1,3]dioxolan-2-yl, pyrrol-1-ylmethyl, 3,4-dimethoxy-benzyl,4-hydroxyphenyloxymethyl, phenylcarbonylmethyl, 4-fluoro-phenoxymethyl,2,2-dimethyl-propyl, 4-fluoro-phenylsulfanylmethyl, hydroxymethyl,formyl, 4-fluoro-phenylamino-methyl, imidazol-1-ylmethyl,dimethylaminomethyl, morpholin-4-ylmethyl, biphenyl-4-ylmethyl,ethoxycarbonyl, carboxy, 4-hydroxybenzyl, furan-2-ylmethyl,thiophen-2-ylmethyl, thiophen-3-ylmethyl, 1-methyl-pyrrol-2-ylmethyl,pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl,4-acetylaminobenzyl, 4-amino-benzyl, 4-nitro-benzyl,4-acetylamino-3-methoxy-benzyl, 4-amino-3-methoxy-benzyl,3-acetylamino-4-methoxy-benzyl, 3-amino-4-methoxy-benzyl, allyl,isopropenyl or halogenmethyl, and R² and R³ are methyl or together are amethylen group bridging the oxygen atoms to which they are attached andR⁴ is hydrogen or methyl.

[0016] Very preferred compounds are compounds of formula I, wherein R¹is 4-methoxy-benzyl, phenyl, benzyl, cyclopropylmethyl, 4-fluoro-benzyl,3,4-dihydro-1H-isoquinolin-2-ylmethyl, 4-methoxy-benzyloxymethyl,4-acetylaminophenyl-sulfanyl-methyl, 4-trifluoromethyl-phenoxymethyl,4-amino-phenoxymethyl, allyloxymethyl, 3,4-dimethoxy-benzyl,4-hydroxybenzyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl,pyridin-4-ylmethyl, 4-acetylaminobenzyl, 4-amino-benzyl,4-acetylamino-3-methoxy-benzyl, 4-amino-3-methoxy-benzyl,3-acetylamino-4-methoxy-benzyl, 3-amino-4-methoxy-benzyl or aryl methyland R²and R³ are both methyl and R⁴ is hydrogen.

[0017] Most preferred compounds are compounds of formula I, wherein R¹is 4-methoxy-benzyl, benzyl, cyclopropylmethyl, 4-fluoro-benzyl,3,4-dihydro-1H-isoquinolin-2-ylmethyl, 4-amino-phenoxymethyl,4-hydroxybenzyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl,pyridin-4-ylmethyl, 4-acetylaminobenzyl, 4-amino-benzyl,4-acetylamino-3-methoxy-benzyl, 4-amino-3-methoxy-benzyl,3-acetylamino-4-methoxy-benzyl, 3-amino-4-methoxy-benzyl and R² and R³are both methyl and R⁴ is hydrogen

[0018] Preferred compounds of the present invention include:

[0019]5-[6,7-Dimethoxy-2-(4-methoxy-benzy)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0020]5-(6,7-Dimethoxy-2-phenyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,

[0021]5-(2-Benzyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,

[0022]5-(2-Cyclopropylmethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,

[0023]5-[2-(4-Fluoro-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0024]5-[2-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0025]5-[6,7-Dimethoxy-2-(4-methoxy-benzyloxymethyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0026]N-{4-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethylsulfanyl]-phenyl}-acetamide,

[0027]5-[6,7-Dimethoxy-2-(4-trifluoromethyl-phenoxymethyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0028]5-[2-(4-Amino-phenoxymethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0029]5-(2-Allyloxymethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,

[0030]5-[6,7-Dimethoxy-2-(2-phenyl-[1,3]dioxolan-2-yl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0031]5-[6,7-Dimethoxy-2-pyrrol-1-ylmethyl-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0032]5-[2-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0033]4-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethoxy]-phenol,

[0034][4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-yl]-phenyl-methanone,

[0035]5-[2-(4-Fluoro-phenoxymethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0036]5-[2-(2,2-Dimethyl-propyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0037]5-[2-(4-Fluoro-phenylsulfanylmethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0038][4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-y-]-methanol,

[0039]4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-carbaldehyde

[0040]5-(2-[(4-Fluoro-phenylamino)-methyll-6,7-dimethoxy-benzofuran-4-ylmethyll-pyrimidine-2,4-diamine,

[0041]5-(2-lmidazol-1-ylmethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,

[0042]5-(2-Dimethylaminomethyl-6,7-dimethoxy-benzoturan-4-ylmethyl)-pyrimidine-2,4-diamine,

[0043]5-(6,7-Dimethoxy-2-morpholin-4-ylmethyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,

[0044]5-(2-Biphenyl-4-ylmethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,

[0045]4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-3-methyl-benzofuran-2-carboxylicacid,

[0046]4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-3-methyl-benzofuran-2-carboxylicacid ethyl ester,

[0047]5-[6,7-Dimethoxy-2-((4-chlorobenzyl)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0048]5-[6,7-Dimethoxy-2-(1-naphthylmethyl)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0049]5-[6,7-Dimethoxy-2-(2-propenyl)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0050] 5-(6,7-D imethoxy-2-trifluoromethylbenzofuran-4-ylmethyl )pyrimidin e-2,4-diamine,

[0051]5-[6,7-Dimethoxy-2-(2,2-dimethylpropan1-one)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0052] 5-[6,7-Dimethoxy-2-(cyclopropylcarbonyl)benzofuran-4-ylmethylpyrmidine-2,4-diamine,

[0053]5-[6,7-Dimethoxy-2-(4-methoxyphenyl-methanone)benzofuran-4-ylmethyllpyrimidine-2,4-diamine,

[0054]5-[6,7-Dimethoxy-2-(4-chlorophenyl-methanone)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0055]5-[6,7-Dimethoxy-2-(4-fluorophenyl-methanone)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0056] 5-[6,7-Dimethoxy-2-(1-naphthylmethanone)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0057]5-[6,7-Dimethoxy-2-(2,2-dimethyl-1-hydroxypropyl)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0058]5-(6,7-Dimethoxy-2-(cyclopropylmethanol)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0059]5-[6,7-Dimethoxy-2-(phenylmethanol)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0060]5-[6,7-Dimethoxy-2-((4-methoxyphenylmethanol)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0061]5-[6,7-Dimethoxy-2-((4-chlorophenyl)methanol)-benzofuran-4-ylmethylpyrimidine-2,4-diamine,

[0062]5-[6,7-Dimethoxy-2-((4-fluorophenylmethanol)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0063]5-[6,7-Dimethoxy-2-(1-naphthylmethanol)-benzofuran-4-ylmethyljpyrimidine-2,4-diamine,

[0064]5-[2-(3,4-Dihydro-2H-quinolin-1-ylmethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0065]5-[6,7-Dimethoxy-2-(tetrazol-5-ylmethyl)benzofuran-4-ylmethyljpyrimidine-2,4-diamine,

[0066]5-[6,7-Dimethoxy-2-(indol-1-ylmethyl)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0067]5-[6,7-Dimethoxy-2-(imidazol-1-ylcarbonyl)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,

[0068]5-(2-Furan-2-ylmethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,

[0069]5-(6,7-Dimethoxy-2-thiophen-2-ylmethyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,

[0070]5-[6,7-Dimethoxy-2-(1-methyl-1H-pyrrol-2-ylmethyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0071]5-(6,7-Dimethoxy-2-pyridin-2-ylmethyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,

[0072] 5-(6,7-Dimethoxy-2-pyridin-3-ylmethyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,

[0073]5-(6,7-Dimethoxy-2-pyridin-4-ylmethyl-benzoturan-4-ylmethyl)-pyrimidine-2,4-diamine,

[0074]4-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-phenol,

[0075]N-{4-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-phenyl}-acetamide,

[0076]5-[2-(4-Amino-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0077]5-[6,7-Dimethoxy-2-(4-nitro-benzyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0078]N-{4-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-2-methoxy-phenyl}-acetamide,

[0079]5-[2-(4-Amino-3-methoxy-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0080]N-{5-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-2-methoxy-phenyl}-acetamide,

[0081]5-[2-(3-Amino-4-methoxy-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,

[0082]5-(6,7-Dimethoxy-2-thiophen-3-ylmethyl-benzofauran-4-ylmethyl)-pyrimidine-2,4-diamine,

[0083] and pharmaceutically acceptable salts and N-oxides thereof.

[0084] The expression pharmaceutically acceptable salts encompasseseither salts with inorganic acids or organic acids like hydrohalogenicacids, e.g. hydrochloric or hydrobromic acid; sulfuric acid, phosphoricacid, nitric acid, citric acid, formic acid, acetic acid, maleic acid,tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the likeor in case the compound of formula I is acidic in nature with aninorganic base like an alkali or earth alkali base, e.g. sodiumhydroxide, potassium hydroxide, calcium hydroxide etc.

[0085] Because of their ability to inhibit Gram positive and Gramnegative bacteria, the described compounds can be used for the treatmentof diseases which are associated with an infection by such type ofpathogens. They are valuable anti-infectives.

[0086] The compounds can be administered orally, rectally, parenterally,e.g. by intravenous, intramuscular, subcutaneous, intrathecal ortransdermal administration or sublingually or as ophthalmic preparationor administered as aerosol. Examples of applications are capsules,tablets, orally administered suspensions or solutions, suppositories,injections, eye-drops, ointments or aerosols/nebulizers.

[0087] Preferred applications are intravenous, intra-muscular, or oraladministrations as well as eye drops. The dosage used depends upon thetype of the specific active ingredient, the age and the requirements ofthe patient and the kind of application. Generally, dosages of 0.1-50mg/kg body weight per day are considered. The preparations withcompounds of formula I can contain inert or as well pharmacodynamicallyactive excipients like sulphonamides. Tablets or granules, for example,could contain a number of binding agents, filling excipients, carriersubstances or diluents.

[0088] These compositions may be administered in enteral or oral forme.g. as tablets, dragees, gelatine capsules, emulsions, solutions orsuspensions, in nasal form like sprays or rectally in form ofsuppositories. These compounds may also be administered inintramuscular, parenteral or intraveneous form, e.g. in form ofinjectable solutions.

[0089] These pharmaceutical compositions may contain the compounds offormula I as well as their pharmaceutically acceptable salts incombination with inorganic and/or organic excipients which are usual inthe pharmaceutical industry like lactose, maize or derivatives thereof,talcum, stearinic acid or salts of these materials.

[0090] For gelatine capsules vegetable oils, waxes, fats, liquid orhalf-liquid polyols etc. may be used. For the preparation of solutionsand syrups e.g. water, polyols, saccharose, glucose etc. are used.Injectables are prepared by using e.g. water, polyols, alcohols,glycerin, vegetable oils, lecithin, liposomes etc. Suppositories areprepared by using natural or hydrogenated oils, waxes, fatty acids(fats), liquid or half-liquid polyols etc.

[0091] The compositions may contain in addition preservatives,stabilisation improving substances, viscosity improving or regulatingsubstances, solubility improving substances, sweeteners, dyes, tasteimproving compounds, salts to change the osmotic pressure, buffer,antioxidants etc.

[0092] The compounds of formula I may also be used in co-therapy withone or more other therapeutically used classes of antimicrobialsubstances, for example, β-lactams e.g. penicillins and cephalosporins;glycopeptides; quinolones; tetracyclines; aminoglycosides; macrolidesetc.

[0093] The dosage may vary within wide limits but should be adapted tothe specific situation. In general the dosage given in oral form shoulddaily be between about 3 mg and about 4 g, preferably between about 0.2g and about 4 g, especially preferred between 0.2 g and 2 g per adultwith a body weight of about 70 kg. The dosage should be administeredpreferably in 1 to 3 doses per day which are of equal weight. As usualchildren should receive lower doses which are adapted to body weight andage.

[0094] The invention also relates to a process for the manufacture ofcompounds of formula I

[0095] wherein

[0096] R¹, R², R³ and R⁴ have the meaning given in formula I above,which process comprises reacting—as depicted in Scheme 1—a compound ofthe general formula III (obtained from a gallate derivative II: eitherby Friedel-Crafts acylation, or via a Vilsmeyer aldehyde synthesis (K.Hayashi, K. Tokura, K. Okabe, K. Yamamoto, and K Tawara, Chem. Pharm.Bull. 1982, 30, 2860-2869), or by formylation withdichloromethoxymethane, see experimental part), with boron trichlorideor boron tribromide at temperatures between −70° C. and 0° C. Themethoxy group adjacent to the acyl group is thereby selectively cleaved,to yleld ortho-acyl phenol derivatives of the general formula IV:

[0097] Subsequently, the compounds IV, wherein R², R³, and R⁴ have themeaning given in formula I above, are reacted with et-bromomethylketones R⁵—CO—CH₂Br V in the presence of potassium carbonate, to yleld2-acylated benzofuran derivatives VI (Scheme 2)

[0098] whereby in formula V R⁵ represents straight or branched chainlower alkyl with 1 to 5 carbon atoms; cycloalkyl with 3 to 6 carbonatoms; aryl or heteroaryl, the aryl and heteroaryl group may be mono-,di- or tri-substituted with halogen, amino, lower alkyloxy, loweralkylcarbonylamino, arylcarbonylamino, whereby these substituents may bethe same or different; straight or branched chain lower alkenyl with 2to 6 carbon atoms.

[0099] The carbonyl group of VI can then be removed selectively byreducing it with sodium cyanoborohydride in the presence oftrimethylsilyl chloride, to yleld the benzofuran ester derivatives IX,wherein R¹, R², R³, and R⁴ have the meaning given in formula I.

[0100] Alternatively, benzofurans of the general structure IX can beobtained by reacting IV with an (x-bromo-ester derivativeR⁶OCO—CH(Br)—R⁷ VlI (R⁶ is tert-butyl, and R⁷ may be hydrogen ortert-butoxycarbonyl), again in the presence of carbonate, to givebenzofuran dicarboxylates of the formula VIII, whereby R², R³, and R⁴have the meaning given in formula I, and R⁶ represents the tert-butylgroup. The latter can be cleaved selectively with trifluoroacetic acid,and may then be reduced preferentially with diborane. The resultingprimary alcohol is then converted into a leaving group, e.g. a tosylate,which is then displaced by a nucleophile Re, such as anitrogen-containing heteroaromatic moiety to yleld IX wherein R¹ equalsR⁸CH₂—.

[0101] If the acyl group in formula VI (Scheme 2) is to be preserved,i.e. if in the final product (formula I) R¹ represents an acyl group(cycloalkylcarbonyl, arylcarbonyl etc.), it may be protected as anethylene ketal, as set forth in structure X (Scheme 3):

[0102] In a third alternative approach described in Scheme 4, phenol XI(Wipf, P.; Weiner, W. S. J. Org. Chem. 1999, 64, 5321-5324) is reactedwith a propargylic alcohol derivative XII under Mitsunobu conditions(diethyl azodicarboxylate and triphenyl phosphine) to afford the phenylethers XIII. After cleaving off the trimethylsilyl protecting group withpotassium carbonate, the resulting free acetylenes can be rearranged, asdescribed previously (Koch-Pomeranz, U.; Hansen, H.-J.; Schmid, H. Helv.Chim. Acta 1973, 56, 2981-3004), to benzofurans IX.

[0103] The manufacturing process then continues as depicted in Scheme 5.The ester function of the general substructure XIV (consisting of eitherIX or X) is reduced to an aldehyde XVI, either directly, with anorganoaluminum hydride reagent, or in two steps, via the primary alcoholXV.

[0104] Finally, the aldehyde group is transformed into thediaminopyrimidine ring, employlng the standard technology outlined inScheme 6.

[0105] Thus, compounds of formula I can be obtained; if R¹ represents anacyl group, i.e. structure XVII has been the intermediate, the finalelaboration includes an acid-induced removal of the ketal protectinggroup.

[0106] Access to an alternative array of substituents can be gained byproceeding according to Scheme 7: The diester VII (Schemes 2 and 7), ifR⁶ represents a tert.-butyl group, can be cleaved selectively withtrifluoroacetic acid, ylelding VIII, R⁶=H. This carboxylic acid may thenbe reduced with diborane to the primary alcohol IX, R¹=CH₂OH.

[0107] Treatment with thionyl chloride affords IX, R¹=CH₂Cl. This veryactive halide can now be employed as one component in the Lewis acid(preferably ZnCl₂) catalysed Friedel-Craft's alkylation, the R⁵component being either an electron-rich aryl or heteroaryl group whichmay be mono-, di- or tri-substituted with halogen, amino, loweralkyloxy, lower alkylcarbonylamino, arylcarbonylamino, such as phenol,1,2-dimethoxybenzene, 2-methoxyphenacetin, furan, thiophene,1-methylpyrrol. The product is compound IX, wherein R¹, R², R³, and R⁴have the meaning given in formula I

[0108] Yet another alternative to 2-substituted benzofurans is describedin Scheme 8:

[0109] Here the same ester VII, R⁶=tert.-butyl, is cleaved withtrifluoroacetic acid, and the resulting carboxylic acid VII, R⁶=H can becoupled in peptide fashion with primary or secondary amines R⁸,producing the carboxamides XVIII, wherein R₈ may be a mono- or di-loweralkylamino group, aminoaryl or heterocycle acylated at the secondaryamine group, such as morpholin-4-yl or tetrahydroisoquinoline-2-yl andR², R³, and R⁴ have the meaning given in formula I.

[0110] A different pattern of substituents results, when the free acidVIII, R⁶=H is reduced, as in Scheme 7, to the primary alcohol XIX, R⁹=H(this compound is identical with IX, R¹=CH₂OH of Scheme 7). This alcoholin turn may be transformed into ether derivatives XIX by alkylating itssodium salt with very reactive halides such as allyl bromide or benzylbromide, wherein R⁹ may be lower alkyl, lower alkenyl, or arylmethyl an,R³, and R⁴ have the meaning given in formula I

[0111] The final elaboration of the intermediates IX, XVIII and XIX ofthe Schemes 7 and 8 into diaminopyrimidines is then carried out inanalogy to the Schemes 5 and 6.

[0112] If so desired, the operations summarised in the Schemes 7 and 8may be carried out in a more convergent fashion closer to the end of thesynthesis:

[0113] Thus, as in Scheme 9, from the allyl protected product XX(obtained from XIX, R⁹=allyl, in Scheme 8 by construction of thepyrimidine ring according to Schemes 5 and 6) the hydroxymethl group canbe liberated by isomerising of the allyl group with Pd(PPh₃)₄ and thenhydrolizing the resulting enol ether. Treatment with thionyl chlorideaffords the reactive chloride XXI, which, in turn can be employed as aFriedel-Craft's component as described in Scheme 7, or which can be usedto O- N- or S-alkylate with HXR¹⁰, wherein X may be one oxygen or onenitrogen or one sulfur and R10 alkyl or aryl groups such as phenols,primary or secondary alkyl- or dialkylamines and aryl(alkyl)amines,thiophenols, pyrrol, indol, imidazol or tetrazol to yleld compounds offormula I.

[0114] An even more convergent approach to is outlined in Scheme 10:

[0115] Here, the demethylated phenol XXII (G. Rey-Bellet and R. ReinerHelv. Chim. Acta 1970, 53, 945) is treated with α-chlorinated aldehydes(or ketones) XXIII wherein R¹ and R⁴ have the meaning given in formulaI, in the presence of potassium carbonate, ylelding the final products Idirectly.

[0116] Another convergent approach (Scheme 11) consists in brominatingthe phenol XXIV and coupling the resulting bromophenol XXV withacetylenic component XXVI as described in the literature (J. Org. Chem.1996, 61, 9280-9288; Bioorg. Med. Chem. 1999, 7, 6, 1131-1140).

[0117] The coupled acetylene then closes spontaneously to thecorresponding benzofuran XXVII.

Examples Abbreviations

[0118] ACN: Acetonitrile

[0119] ATCC: American type culture collection

[0120] DEAD: Diethyl azodicarboxylate

[0121] DMF: Dimethyl formamide

[0122] DMSO: dimethyl sulfoxide

[0123] EtOH: Ethanol

[0124] ESI: Electrospray ionisation

[0125] FC. Flash chromatography

[0126] HPLC: High performance liquid chromatography

[0127] MeOH: methanol

[0128] MS: Mass spectrometry

[0129] NMR: Nuclear magnetic resonance

[0130] RedAl: Sodium bis(2-methoxyethoxy)aluminum hydride

[0131] tBuOK: Potassium tert-butoxide

[0132] TBME: tert-Butyl methyl ether

[0133] TFA: Trifluoroacetic acid

[0134] THF: Tetrahydrofuran

[0135] TLC: Thin layer chromatography

[0136] TMSCI: rimethyl chlorosilane

General Procedure A: Formylation

[0137] Under argon at −20° C., to a solution of compound II (1.0 eq.) indry CH₂Cl₂ was added dichloromethylmethyl ether (1.5 eq.). SnCl₄ (1.0eq.) was added dropwise over a period of 30 min, while maintaining theinside temperature at −20° C. After the addition, the mixture wasallowed to slowly warm up to room. After disappearance of the startingmaterial (TLC), the reaction mixture was again cooled to −10° C. andquenched by slowl addition of NaHCO₃. The organic phase was collected,the aqueous phase was extracted with three portions of tert-butyl methylether (TBME), the combined organic phases were washed with brine, driedwith MgSO₄ and the solvents removed under reduced pressure to givecompound III.

Example 1

[0138] Methyl 2-formyl-3,4,5-trimethoxybenzoate was obtained as a yellowfoam (39.0 g, 90%, 85% HPLC purity) by reacting methyl3,4,5-trimethoxybenzoate (36.0 g) with dichloromethylmethyl ether (27.0g, 1.5 eq.) and SnCl₄ (41.5 g, 1.0 eq). The product, which is ratherunstable, was directly used for the next step.

[0139] NMR CDCl₃ 300 MHz δ in ppm J in Hz: 10.28 (s, 1H, COH), 6.93 (s,1H, Ar), 3.96 (s, 3H, OMe), 3.93 (s, 3H, OMe), 3.89 (s, 6H, 2 OMe).

General Procedure B Demethylation

[0140] Under argon at −10°C., to a solution of compound III (1 eq.) inmethylene chloride, BBr₃ (0.5 eq.) was added over a period of 20 min,such that the temperature was not exceeding 0° C. The mixture wasstirred at 0° C., until disappearance of the starting material. Thereaction mixture was poured into ice-water and the aqueous layer wasextracted with two portions of TBME. The combined organic phases werewashed with water, dried with MgSO₄, and the solvents evaporated underreduced pressure to give compound IV.

Example 2

[0141] Methyl 2-formyl-3-hydroxy-4,5-dimethoxy-benzoate (36.8 g, 98%,88% HPLC purity) was obtained as a white crystalline compound byreacting methyl 2-formyl-3,4,5-trimethoxybenzoate (39.5 g) with BBr₃(7.5 ml, 0.5 eq.).

[0142] NMR CDCl₃ 300 MHz δ in ppm J in Hz: 12.28 (s, 1H, OH), 10.26 (s,1H, COH), 6.57 (s, 1H, Ar), 4.01 (s, 3H, OMe), 3.98 (s, 6H, 2 OMe).

General Procedure C Synthesis of Benzofurans

[0143] Under argon, compound IV (1 eq.) was dissolved in DMF or toluene(Fluka on 4 Å Mol. sieve), K₂CO₃ powder (2.4 eq.) and in some casestetrabuthylammonium bromide (0.1 eq.) was added. After 10 min stirringat r.t., a bromoketone V, a bromomalonic ester VII or a α-bromoester VII(1.2 to 1.9 eq.) was added as well as some 4 Å Mol. sieves. The reactionwas stirred 3 h to 24 h at 110° C. The reaction mixture was filtratedand the solvent evaporated. The residual brown oil was dissolved inCH₂Cl₂ and washed with water and brine. The organic layer was dried withMgSO₄, the solvent evaporated to give the compound VI or VIII.

Example 3

[0144] 6,7-Dimethoxy-2-cyclopropylcarbonyl-benzofuran-4-carboxylic acidmethyl ester (128 mg, 59%) was obtained as a yellow solid aftercrystallisation from ethyl acetate by reacting methyl2-formyl-3-hydroxy-4,5-dimethoxy-benzoate (170 mg, 0.70 mmol) with2-bromo-1-cyclopropylethanone (0.138 g, 0.849 mmol) (which waspreviously obtained from the reaction of1-cyclopropyl-vinyloxitrimethylsilane with N-bromosuccinimide), K₂CO₃(170 mg, 1.7 eq.) and tetrabuthylammonium bromide (27 mg, 0.07 mmol)

[0145] NMR CDCl₃ 300 MHz δ in ppm J in Hz: 7.98 (s, 1H, Ar), 7.68 (m,1H, Ar), 4.28 (s, 3H, OMe), 3.93 (s, 3H, OMe), 3.92 (s, 3H, OMe),2.72-2.55 (m, 1H), 1.29-1.25 (m, 2H), 1.09-1.04 (m, 2H).

Example 4

[0146] 6,7-Dimethoxy-2-phenylcarbonyl-benzofuran-4-carboxylic acidmethyl ester (1.1 g, 56%) was obtained as a yellow solid by reactingMethyl 2-formyl-3-hydroxy-4,5-dimethoxy-benzoate (1.5 g, 6.24 mmol) withK₂CO₃ powder (2.07 mg, 14.97 mmol) and phenacyl bromide (2.36 mg, 11.86mmol).

[0147] NMR CDCl₃ 300 MHz δ in ppm J in Hz: 8.04 (s, 1H, Ar), 7.74 (s,1H, Ar), 7.68-7.54 (m, 5H, Ar), 4.37 (s, 3H, OMe), 4.00 (s, 3H, OMe),3.97 (s, 3H, OMe).

[0148] MP: 116-120° C.

Example 5

[0149] 6,7-Dimethoxy-2-(2,2-dimethylpropanoyl)-benzofuran-4-carboxylicacid methyl ester (182 mg, 57%) was obtained as a yellow solid byreacting methyl 2-formyl-3-hydroxy-4,5-dimethoxy-benzoate (250 mg, 1.04mmol) with K₂CO₃ powder (338 mg, 2.44 mmol) and 1-bromopinacolon (265μl, 1.96 mmol).

[0150] NMR CDCl₃ 300 MHz δ in ppm J in Hz: 8.04 (s, 1H, Ar), 7.72 (s,1H, Ar), 4.35 (s, 3H, OMe), 3.98 (s, 3H, OMe), 3.96(s, 3H, OMe), 1.45(s, 9H, tert-Bu)

[0151] MP 104-108° C.

Example 6

[0152] 6,7-Dimethoxy-2-tert-butoxycarbonyl-benzofuran-4-carboxylic acidmethyl ester (100 mg, 37%) was obtained as a yellow solid by reactingmethyl 2-formyl-3-hydroxy-4,5-dimethoxy-benzoate (200 mg, 0.83 mmol)with K₂CO₃ powder (172 mg, 1.24 mmol), tetrabuthylammonium bromide (27mg, 0.08 mmol) and bromomalonic acid tert-butyl ester (294 mg, 1.00mmol).

General Procedure D: Reduction of the Ketone

[0153] Under argon at 0° C., to a solution of the ketone VI (1 eq.) infreshly distilled THF trimethylsilyl chloride (10 eq.), 4 Å Mol sievepowder and then sodium cyanoborohydride (10 eq.) were added. Thereaction was complete after stirring it for 5 h to 24 h at r.t.Dichloromethane was added to the reaction mixture, which was thenfiltrated through celite. After several washings of the residue withCH₂Cl₂, the filtrate was washed with water and brine, dried with MgSO₄and the solvents evaporated to give compound IX.

Example 7

[0154] 6,7-Dimethoxy-2-cyclopropylmethyl-benzofuran-4-carboxylic acidmethyl ester (94 mg, 90%) was obtained as a glassy solid by reactingtrimethylsilyl chloride (46 μl, 3.61 mmol) and sodium cyanoborohydride(240 mg, 3.61 mmol).

[0155] MS ESI: 291 (M+H).

Example 8

[0156] 6,7-Dimethoxy-2-phenylmethyl-benzofuran-4-carboxylic acid methylester (186 mg, 95%) was obtained as a glassy solid, after purificationby flash chromatography (Rf 0.66, 3:2, hexane/ethyl acetate) by reacting6,7-dimethoxy-2-phenylcarbonyl-benzofuran-4-carboxylic acid methyl ester(200 mg, 0.588 mmol) with sodium cyanoborohydride (370 mg, 5.88 mmol)and trimethylsilyl chloride (743 ml, 5.88 mmol).

[0157] MS ESI+: 365 (M+K), 349 (M+Na), 327 (M+H), 295 (M-OMe) NMR CDCl₃300 MHz δ in ppm J in Hz: 7.56 (s, 1H, Ar), 7.33-7.26 (m, 5H, Ar), 6.91(s, 1H, Ar), 4.24 (s, 3H, OMe), 4.13 (s, 2H, CH₂Ar), 3.93 (s, 3H, OMe),3.91 (s, 3H, OMe).

Example 9

[0158] 6,7-Dimethoxy-2-(2,2-dimethylpropyl)-benzofuran-4-carboxylic acidmethyl ester (180 mg, 94%) was obtained as a glassy solid by reacting6,7-dimethoxy-2-(2,2-dimethylpropanoyl)-benzofuran-4-carboxylic acidmethyl ester (200 mg, 0.62 mmol) with sodium cyanoborohydride (392 mg,6.24 mmol) and trimethylsilyl chloride (789 μl, 6.24 mmol).

[0159] NMR CDCl₃ 300 MHz δ in ppm J in Hz: 7.57 (s, 1H, Ar), 6.92 (s,1H, Ar), 4.29 (s, 3H, OMe), 3.95 (s, 3H, OMe), 3.94(s, 3H, OMe), 2.66(s, 2H, CH₂), 1.03 (s, 9H, tert-Bu)

General Procedure E: Alternative Route to Obtain Benzofuran DerivativesIX

[0160] Compound Xl (1 eq.) was reacted with compound XII (1 eq.)(obtained by sodium borohydride reduction of the corresponding ketone)as described previously (Wipf, P.; Weiner, W. S. J. Org. Chem. 1999, 64,5321-5324) to give compound XIII.

Example 10

[0161]3-(1-Cyclopropyl-trimethylsilylprop-2-ynyloxy)-4,5-dimethoxy-benzoicacid methyl ester was obtained as a colorless oil in 60% yleld from1-cyclopropyl-3-(trimethylsilyl)prop-2yn-1-ol. The same compound canalso be obtained by a copper-1 (CuCl)-catalyzed process as described byGodfrey et al.(Godfrey Jr., J. D. et al, Tetrahedron Lett. 1994, 35,6405-6408).

[0162] MS: M⁺362.

[0163] Ether XIII (1 eq.), K₂CO₃ (3 eq.) and KF (3 eq.) were dissolvedin methanol. The mixture was stirred and the reaction was monitored byTLC. After 25 minutes the reaction was complete and the mixture waspartitioned between of water and a mixture of hexane/ethyl acetate 4:1.The layers were separated, the aqueous layer was washed three times withof hexane/ethyl acetate 4:1. The organic layers were combined andevaporated to give the resulting acetylene which was used directly forthe next step.

Example 11

[0164] 3-(1-Cyclopropyl-prop-2-ynyloxy)-4,5-dimethoxy-benzoic acidmethyl ester (17.5 g, 71%) was obtained as a white solid bycrystallization from hexane/ether by reacting3-(1-cyclopropyl-trimethylsilylprop-2-ynyloxy)-4,5-dimethoxy-benzoicacid methyl ester (30.87 g, 80 mmol) with K₂CO₃ (30 g) and KF (30 g)17.5 g, 60.4 mmol, 71%. mp. 93-94° C.

[0165] The acetylene previously obtained (1 eq.) was dissolved in DMF(tech.) containing 5% N,N-diethylaniline and the reaction mixture wasstirred for 2 h at 150° C. After work-up and crystallisation from etherthe compound IX was obtained.

Example 12

[0166] 6,7-Dimethoxy-2-cyclopropylmethyl-benzofuran-4-carboxylic acidmethyl ester (50%) was obtained as white-red crystals by reacting in anintramolecular fashion3-(1-cyclopropyl-prop-2-ynyloxy)-4,5-dimethoxy-benzoic acid methyl ester(88 g, 0.316 mol)

[0167] NMR CDCl₃ 300 MHz δ in ppm J in Hz: 7.57 (s, 1H, Ar), 7.00 (m,1H, Ar), 4.28 (s, 3H, OMe), 3.95 (s, 3H, OMe), 3.94 (s, 3H, OMe), 2.70(d, 2H, J=6.6), 1.95-1.75 (m, 1H), 0.62-0.59 (m, 2H), 0.29-0.25 (m, 2H).

General Procedure F Reduction of the Ester to Alcohol

[0168] Under argon, ester XIV (1 eq.) was dissolved in THF freshlydistilled and treated with LiAlH₄ (3 eq.) The reaction was stirred at60° C. for 2 h until disappearance of the starting material. Thereaction was quenched with 0.5 N HCl, the white precipitate filtratedand washed with ether. The organic layer was dried with MgSO₄ and thesolvents evaporated to give the alcohol XV.

Example 13

[0169] (6,7-Dimethoxy-2-phenylmethyl-benzofuran-4-yl)-methanol (82 mg,90%) was obtained by reacting6,7-dimethoxy-2-phenylmethyl-benzofuran-4-carboxylic acid methyl ester(100 mg, 0.30 mmol) with LiAlH₄ (33 mg, 0.91 mmol).

[0170] MS ESI: 321 (M+Na).

General Procedure G Oxidation of the Alcohol to Aldehyde

[0171] Under argon, alcohol XV (1 eq.) was dissolved in dichloromethaneand MnO₂ (10 eq.) was added. The reaction mixture was stirred 3 h atr.t. and filtrated over celite. The celite was washed with excess ofCH₂Cl₂, the solvent evaporated to give the aldehyde XVI.

Example 14

[0172] 6,7-Dimethoxy-2-phenylmethyl-benzofuran-4-carbaldehyde (119 mg,62%) was obtained as an oil by reacting(6,7-dimethoxy-2-phenylmethyl-benzofuran-4-yl)-methanol (192 mg, 1.29mmol) with MnO₂ (1.121 g, 12.90 mmol)

General Procedure H Reduction of the Ester to the Aldehyde

[0173] Under argon at 0° C., to a solution of sodiumdihydro-bis(2-methoxyethoxy)-aluminate (Red Al, ca. 3.5 M in toluene)(3.1 eq.) in toluene (over 4 Å Mol. sieve) was added dropwise, within 30min, morpholine (3.4 eq.) in toluene. The resulting solution was stirredfor 30 min, and it was slowly added at −30° C. to a solution of theester XIV (1 eq.) in toluene. The reaction mixture was then stirred for4 h at −15° C. and quenched by addition of 3N NaOH and stirred until itreached r.t. The reaction mixture was then diluted with ice water andextracted with toluene. The organic layer was washed with water, driedover MgSO₄ and the solvent evaporated to give compound XVI.

Example 15

[0174] 6,7-Dimethoxy-2-cyclopropylmethyl-benzofuran-4-carbaldehyde (1.16g, 66%) was obtained as light yellow crystals after crystallisation in5:1 ethyl acetate/hexane by reacting sodiumdihydro-bis(2-methoxyethoxy)-aluminate (Red Al, ca. 3.5M in toluene)(6.5 ml, 22.6 mmol) with morpholine (2.1 ml, 24.0 mmol) and6,7-dimethoxy-2-cyclopropylmethyl-benzofuran-4-carboxylic acid methylester (2.05 g, 7.0 mmol) NMR CDCl₃ 300 MHz δ in ppm J in Hz: 10.06 (s,1H, COH), 7.32 (s, 1H, Ar) 7.51 (s, 1H, Ar), 4.35 (s, 3H, OMe), 3.97 (s,3H, OMe), 2.72 (d, 2H, J=7.1), 1.19-1.17 (m, 1H), 0.64-0.60 (m, 2H),0.29-0.27 (m, 2H).

[0175] MP 44-46° C.

Example 16

[0176] 6,7-Dimethoxy-2-(2,2dimethlypropyl)-benzofuran-4-carbaldehyde(115 mg, 80%) was obtained as an oil from the reaction of sodiumdihydro-bis(2-methoxyethoxy)-aluminate (Red Al, ca. 3.5M in toluene)(500 μl, 1.62 mmol) with morpholine (159 μl, 1.83 mmol) and6,7-dimethoxy-2-(2,2dimethlypropyl)-benzofuran-4-carboxylic acid methylester (160 mg, 0.522 mmol).

General Procedure I Coupling With Anilinopropionitrile

[0177] Under argon at 10° C., the aldehyde XVI (1 eq.) was dissolved inDMSO (25 ml) and freshly crystallized 3-anilinopropionitrile (1.1 eq.)was added. Potassium tert-butoxide (1.15 eq.) was added in portions tothe reaction mixture. The solution was stirred at 10° C. for 1 h and atr.t. for 3 h. The reaction mixture was poured into ice-water andextracted 3 times with ethyl acetate. The organic layer was washed withwater and dried over MgSO₄. The solvents were evaporated to givecompound XVII.

Example 17

[0178]3-Anilino-2-(6,7-dimethoxy-2-cyclopropylmethyl-benzofuran-4-ylmethyl)-acrylonitrile(1.87 g, 49%) was obtained after purification by flash chromatography2:3 ethyl acetate/hexane to as a yellow oil from the reaction of6,7-dimethoxy-2-cyclopropylmethyl-benzofuran-4-carbaldehyde (2.6 g, 9.9mmol) with 3-anilinopropionitrile (1.44 g, 10.9 mmol) and potassiumtert-butoxide (1.28 g, 11.5 mmol)

Example 18

[0179]3-Anilino-2-(6,7-dimethoxy-2-phenylmethyl-benzofuran-4-ylmethyl)-acrylonitrile(88 mg, 53%) was obtained after purification by flash chromatography(2:3 ethyl acetate/hexane) as a yellow oil by reacting of6,7-dimethoxy-2-phenylmethyl-benzofuran-4-carbaldehyde (119 mg, 0.40mmol) with 3-anilinopropionitrile (58 mg, 0.44 mmol) and potassiumtert-butoxide (52 mg, 0.46 mmol)

[0180] MS ESI: 423 (M−H).

Example 19

[0181]3-Anilino-2-(6,7-dimethoxy-2-(2,2-dimethlypropyl)-benzofuran-4-ylmethyl)-acrylonitrile(91 mg, 54%) was obtained after purification by flash chromatography(2:3 ethyl acetate/hexane) as a yellow oil by reacting6,7-dimethoxy-2-(2,2dimethlypropyl)-benzofuran-4-carbaldehyde (115 mg,0.42 mmol) with 3-anilinopropionitrile (60 mg, 0.46 mmol) and potassiumtert-butoxide (54 mg, 0.48 mmol)

[0182] MS ESI: 427 (M+Na).

General Procedure J Cyclisation With Guanidine

[0183] Under argon, to a solution of guanidine hydrochloride (3 eq.) inethanol potassium tert-butoxide (3 eq.) was added and the mixture wasstirred for 15 min. The fine precipitate was filtered through celiteunder argon and the filtrate was added to a solution of compound XVII (1eq.) in ethanol. The reaction mixture was stirred under refluxconditions for 8h. After cooling the reaction to r.t., then to −20° C.compound I precipitated.

Example 20

[0184]5-(2-Cyclopropylmethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(1.16 g, 96%) was obtained as a white-yellow precipitate by reactingguanidine hydrochloride (1.37 g, 14.44 mmol), potassium tert-butoxide(1.62 g, 14.44 mmol) and3-anilino-2-(6,7-dimethoxy-2-cyclopropylmethyl-benzofuran-4-ylmethyl)acrylonitrile(1.87 g, 4.81 mmol)

[0185] NMR CD₃OD 500 MHz δ in ppm J in Hz: 6.95-7.35 (m, 1H, Ar), 6.78(s, 1H, Ar) 6.44 (s, 1H, Ar), 4.03 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.81(s, 2H, CH₂), 2.66 (d, 2H, J=6.8), 1.14-1.04 (m, 1H), 0.59-0.54 (m, 2H),0.28-0.25 (m, 2H).

[0186] MS ISP: 397 (M+Na, 25%), 355 (M+H, 100%); HPLC purity RP C₁₈Dicovery: 98%.

Example 21

[0187]5-(2-Benzyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(20 mg, 36%) was obtained as a white-yellow precipitate by reactingguanidine hydrochloride (40 mg, 0.42 mmol), potassium tert-butoxide (47mg, 0.42 mmol) and3-anilino-2-(6,7-dimethoxy-2-phenylmethyl-benzofuran-4-ylmethyl)-acrylonitrile(59 mg, 0.14 mmol)

[0188] MS ESI: 391 (M+H); HPLC purity RP C₁₈ Dicovery: 97%.

Example 22

[0189]5-(6,7-Dimethoxy-2-(2,2-dimethlypropyl)-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(28 mg, 33%) was obtained as a white-yellow precipitate by reactingguanidine hydrochloride (64 mg, 0.67 mmol), potassium tert-butoxide (75mg, 0.67 mmol) and3-anilino-2-(6,7-dimethoxy-2-(2,2-dimethlypropyl)-benzofuran-4-ylmethyl)-acrylonitrile(91 mg, 0.22 mmol)

[0190] MS ESI: 371 (M+H); HPLC purity RP C₁₈ Dicovery: 99%.

Example 23

[0191] Following general procedure C,2-(biphenyl-4-carboyl)-6,7-dimethoxy-benzofuran-4-carboxylic acid methylester (1.6 g, 95%) was obtained as a yellow solid by reacting methyl2-formyl-3-hydroxy-4,5-dimethoxy-benzoate (1.0 g, 4.16 mmol) with K₂CO₃powder (1.44 mg, 10.4 mmol) and 4-phenyl-phenacylbromid (2.29 g, 8.32mmol).

Example 24

[0192] Following general procedure C,6,7-dimethoxy-2-(4-methoxy-benzoyl)-benzofuran-4-carboxylic acid methylester (0.331 g, 43%) was obtained as a yellow solid by reacting methyl2-formyl-3-hydroxy-4,5-dimethoxy-benzoate (0.5 g, 2.08 mmol) with K₂CO₃powder (0.69 mg, 4.9 mmol) and 2-bromo-4-methoxyacetopenon (0.98 g, 4.16mmol) NMR CDCl₃ 300 MHz δ in ppm J in Hz: 8.01 (d, 2H, Ar), 7.92 (s, 1H,Ar), 7.64 (s, 1H, Ar), 6.94 (d, 2H, Ar), 4.27 (s, 3H, OMe), 3.93 (s, 3H,OMe), 3.90 (s, 3H, OMe), 3.83 (s, 3H, OMe).

Example 25

[0193] Following general procedure C,2-(4-fluoro-benzoyl)-6,7-dimethoxy-benzofuran-4-caboxylic acid methylester (2.37, 82%) was obtained as a yellow solid by reacting methyl2-formyl-3-hydroxy-4,5-dimethoxy-benzoate (2.0 g, 8.32 mmol) with K₂CO₃powder (2.30 mg, 16.62 mmol) and 2-bromo-4-fluoracetopenon (2.71 g,12.49 mmol).

Example 26

[0194] Following general procedure D,2-biphenyl-4-ylmethyl-6,7-dimethoxy-benzofuran-4-carboxylic acid methylester (474 mg, 98%) was obtained as yellow oil by reactingtrimethylsilyl chloride (1.52 ml, 12.0 mmol) and sodium cyanoborohydride(754 mg, 12.0 mmol).

Example 27

[0195] Following general procedure D,6,7-dimethoxy-2-(4-methoxy-benzyl)-benzofuran-4-carboxylic acid methylester (131 mg, 93%) was obtained as yellow oil by reactingtrimethylsilyl chloride (0.341 ml, 2.7 mmol) and sodium cyanoborohydride(169 mg, 2.7 mmol).

[0196] MS ESI 1: 379 (M+Na).

Example 28

[0197] Following general procedure D,2-(4-fluoro-benzyl)-6,7-dimethoxy-benzofuran-4-carboxylic acid methylester (868 mg, 90%) was obtained as yellow oil by reactingtrimethylsilyl chloride (3.64 ml, 28.7 mmol) and sodium cyanoborohydride(1.8 g, 28.7 mmol).

[0198] MS ESI+329 (M−Me).

Example 29 Cleavage of the tBu Ester

[0199] Under argon at 0° C. 6,7-Dimethoxy-benzofuran-2,4-dicarboxylicacid 2-tert-butyl ester 4-methyl ester (10 g, 29.7 mmol) was dissolvedin TFA (23 ml, 297.3 mmol) and the reaction mixture was stirred for 3 hallowing the temperature to reach r.t. The excess of TFA was evaporatedand the resulting pink solid was triturated in ether. The resultingsolid was dissolved in NaHCO₃ saturated solution, the aqueous layer wasextracted with ether then the basic aqueous solution was acidified topH=1 with 6N HCl and the product was extracted with ethyl acetate. Theethyl acetate organic layer was washed with brine, dried over MgSO₄ andthe solvent evaporated to give 6,7-dimethxy-benzofuran-2,4-dicarboxylicacid 4-methyl ester (6.43, 77%) as a white solid.

[0200] MS ESI−279 (M−H).

General Procedure K Coupling With Amines

[0201] Under argon at 0° C., to a solution of the acid6,7-Dimethxy-benzofuran-2,4-dicarboxylic acid 4-methyl ester (1 eq.) inCH₂Cl₂/DMF (20:1) were added HOBt (1.2 eq.), EDC(1.2 eq.), the secondaryor primary amine (1.1 eq.) and finally triethyl amine (3eq.). Thereaction mixture was stirred overnight. Some additional CH₂Cl₂ was addedand the organic layer was washed with HCl 1N, H₂O, NaHCO₃ sat and brine.After drylng the organic layer over MgSO4 the solvent was evaporated togive compound IX.

Example 30

[0202] 2-Dimethylcarbamoyl-6,7-dimethoxy-benzofuran-4-carboxylic acidmethyl ester (1.64 g, 97%) was obtained by reacting give6,7-dimethxy-benzofuran-2,4-dicarboxylic acid 4-methyl ester (1.5 g,5.35 mmol) with HOBt (868 mg, 6.42 mmol) EDC (1.23 g, 6.42 mmol),dimethylamine (480 mg, 5.88 mmol), and Et₃N (2.23 ml, 16.05 mmol).

[0203] MS ESI+: 308 (M+H).

Example 31

[0204]2-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-6,7-dimethoxy-benzofuran-4-carboxylicacid methyl ester (2.09 g, 98%) was obtained by reacting give6,7-dimethxy-benzofuran-2,4-dicarboxylic acid 4-methyl ester (1.5 g,5.35 mmol) with HOBt (868 mg, 6.42 mmol) EDC (1.23 g, 6.42 mmol),tetrahydrosisoquinoline (0.747 ml, 5.88 mmol), and Et₃N (2.23 ml, 16.05mmol).

[0205] MS ESI+: 396 (M+H).

Example 32

[0206] 6,7-Dimethoxy-2-(morpholine-4-carbonyl)-benzofuran-4-carboxylicacid methyl ester (1.85 g, 98%) was obtained by reacting give6,7-dimethxy-benzofuran-2,4-dicarboxylic acid 4-methyl ester (1.5 g,5.35 mmol) with HOBt (868 mg, 6.42 mmol) EDC (1.23 g, 6.42 mmol),morpholine (0.513 ml, 5.88 mmol), and Et₃N (2.23 ml, 16.05 mmol).

[0207] MS ESI+: 350 (M+H).

Example 33

[0208]2-(4-Fluoro-phenylcarbamoyl)-6,7-dimethoxy-benzofuran-4-carboxylic acidmethyl ester (978 mg, 52%) was obtained by reacting give6,7-dimethxy-benzofuran-2,4-dicarboxylic acid 4-methyl ester (1.4 g,4.99 mmol) with HOBt (810 mg, 5.99 mmol) EDC (1.15 g, 5.99 mmol),4-fluoroaniline (0.527 ml, 5.49 mmol), and Et₃N (2.1 ml, 14.98 mmol).

[0209] MS ESI−:372 (M+H).

Example 34 Reduction of the Acid

[0210] Under argon, 6,7-dimethxy-benzofuran-2,4-dicarboxylic acid4-methyl ester (66.46 g, 237 mmol) was dissolved in THF dist. and a 2Msolution of BH₃.DMS (116 ml, 0.260 mmol) was slowly added. The reactionmixture was stirred at reflux overnight. After cooling to r.t thereaction was quenched with MeOH. The solvents were then evaporated andthe resulting oil was dissolved in ethyl acetate. The organic layer waswashed with NaHCO₃ sat., H₂O and brine, dried over MgSO₄.2-Hydroxymethyl-6,7-dimethoxy-benzofuran-4-carboxylic acid methyl ester(34 g, 54%) was obtained as yellow-white solid after purification by FCHexane/ethyl acetate (3:2).

[0211] MS ESI+:267 (M+H).

General Procedure L Coupling With Halogen Derivatives

[0212] Under argon, to a solution of2-hydroxymethyl-6,7-dimethoxy-benzofuran-4-carboxylic acid (1 eq.) inDMF dried over molecular sieve was added portionwise NaH 60% (1.1 eq.).Halogen derivatives XR⁹ (1.05 eq.) were slowly added to the solution.The reaction was stirred 1 h at r.t and was quenched with some H₂O.After evaporation of the DMF the resulting oil was partitioned betweenethyl acetate and NaHCO₃. After extraction of the water layer with ethylacetate the organic layer was washed with H₂O, KHSO₄ 1N and brine, driedover MgSO₄ and the solvents evaporated. The pure compound IX wasobtained after purification by FC hexane/ethyl acetate (4:1).

Example 35

[0213] 2-Allyloxymethyl-6,7-dimethoxy-benzofuran-4-carboxylic acidmethyl ester (10.43 g, 60%) was obtained as a yellow oil by reacting2-hydroxymethyl-6,7-dimethoxy-benzofuran-4-carboxylic acid (15 g, 56.39mmol) with NaH 60% (2.48 g, 62.03 mmol) and allyl bromide (5.01 ml,59.21 mmol).

[0214] LC MS clean but no ionisation.

Example 36

[0215]6,7-Dimethoxy-2-(4-methoxy-benzyloxymethyl)-benzofuran-4-carboxylic acidmethyl ester (480 mg, 40%) was obtained as a crystalline solid byreacting 2-hydroxymethyl-6,7-dimethoxy-benzofuran-4-carboxylic acid (840mg, 3.15 mmol) with NaH 60% (139 mg, 3.47 mmol), K₂CO₃ (436 mg, 3.15mmol) and methoxybenzyl chloride (0.449 ml, 3.31 mmol).

[0216] NMR CDCl₃ 300 MHz □ in ppm J in Hz: 7.61 (s, 1H, Ar), 7.29 (d,2H, Ar), 7.21 (s, 1H, Ar), 6.28 (d, 2H, Ar), 4.61 (s, 2H, CH₂), 4.56 (s,2H, CH₂), 4.28 (s, 3H, OMe), 3.93 (s, 6H, 2×OMe), 3.80 (s, 3H, OMe).

Example 37

[0217] Following general procedure F,(2-biphenyl-4-ylmethyl-6,7-dimethoxy-benzofuran-4-yl)-methanol (395 mg,90%) was obtained as a trasparant oil by reacting2-biphenyl-4-ylmethyl-6,7-dimethoxy-benzofuran-4-carboxylic acid methylester (474 mg, 1.18 mmol) with LiAlH₄ (135 mg, 3.53 mmol).

[0218] MS ESI+: 357 (M−OH).

Example 38

[0219] Following general procedure F,[6,7-dimethoxy-2-(4-methoxy-benzyl)-benzofuran-4-yl]-methanol (79 mg,66%) was obtained as an oil by reacting6,7-dimethoxy-2-(4-methoxy-benzyl)-benzofuran-4-carboxylic acid methylester (131 mg, 0.36 mmol) with LiAlH₄ (28 mg, 0.73 mmol).

[0220] MS ESI+:311 (M−OH).

Example 39

[0221] Following general procedure F,[2-(4-fluoro-benzyl)-6,7-dimethoxy-benzofuran-4-yl]-methanol (709 mg,86%) was obtained as an oil by reacting2-(4-fluoro-benzyl)-6,7-dimethoxy-benzofuran-4-carboxylic acid methylester (868 mg, 2.60 mmol) with LiAlH₄ (197 mg, 5.21 mmol).

[0222] MS ESI+: 299 (M−OH).

Example 40

[0223] Following general procedure F,(2-dimethylaminomethyl-6,7-dimethoxy-benzofuran-4-yl)-methanol (507 g,60%) was obtained as an oil by reacting2-dimethylcarbamoyl-6,7-dimethoxy-benzofuran-4-carboxylic acid methylester (1.0 g, 2.60 mmol) with LiAlH₄ (494 mg, 13.01 mmol).

[0224] MS ESI+: 266 (M+H).

Example 41

[0225] Following general procedure F,[2-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-6,7-dimethoxy-benzofuran-4-yl]-methanol(970 mg, 77%) was obtained as an oil by reacting2-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-6,7-dimethoxy-benzofuran-4-carboxylicacid methyl ester (1.4 g, 3.54 mmol) with LiAlH₄ (537 mg, 14.16 mmol).

[0226] MS ESI+: 354 (M+H).

Example 42

[0227] Following general procedure F,(6,7-dimethoxy-2-morpholin-4-ylmethyl-benzofuran-4-yl)-methanol (800 mg,60%) was obtained as an oil by reacting6,7-dimethoxy-2-(morpholine-4-carbonyl)-benzofuran-4-carboxylic acidmethyl ester (1.52 g, 4.35 mmol) with LiAlH₄ (660 mg, 17.40 mmol).

[0228] MS ESI+:308 (M+H).

Example 43

[0229] Following general procedure F,{2-[(4-fluoro-phenylamino)-methyl]-6,7-dimethoxy-benzofuran-4-yl}-methanol(724 mg, 84%) was obtained as an oil by reacting2-(4-fluoro-phenylcarbamoyl)-6,7-dimethoxy-benzofuran-4-carboxylic acidmethyl ester (974 mg, 2.6 mmol) with LiAlH₄ (495 mg, 13.0 mmol).

[0230] MS ESI+: 330 (M+H) very weak signal.

Example 44

[0231] Following general procedure F,(2-allyloxymethyl-6,7-dimethoxy-benzofuran-4-yl)-methanol (1.76 g, 98%)was obtained as an oil by reacting2-allyloxymethyl-6,7-dimethoxy-benzofuran-4-carboxylic acid methyl ester(1.95 g, 6.36 mmol) with LiAlH₄ (483 mg, 12.73 mmol).

[0232] MS ESI+: 261 (M−OH).

Example 45

[0233] Following general procedure F,(6,7-dimethoxy-2-(4-methoxy-benzyloxymethyl)-benzofuran-4-yl]-methanol(390 mg, 95%) was obtained as an oil by reacting6,7-dimethoxy-2-(4-methoxy-benzyloxymethyl)-benzofuran-4-carboxylic acidmethyl ester (445 mg, 1.15 mmol) with LiAlH₄ (87 mg, 2.30 mmol).

[0234] MS ESI+: 341 (M−OH).

Example 46

[0235] Following general procedure F,(6,7-dimethoxy-2-phenyl-benzofuran-4-yl)-methanol (150 mg, 74%) wasobtained as an oil by reacting6,7-dimethoxy-2-phenylbenzofuran-4-carboxylic acid methyl ester (235 mg,0.735 mmol) with LiAlH₄ (14 mg, 0.377 mmol).6,7-dimethoxy-2-phenylbenzofuran-4-carboxylic acid methyl ester (240 mg,22%) was obtained following the palladium coupling procedure [J. Org.Chem. 1996, 61, 9280-9288; Bioorg. Med. Chem., 1999, 7, 6, 1131-1140] byreacting 2-bromo-3-hydroxy-4,5-dimethoxy-benzoic acid methyl ester (1 g,3.44 mmol) (P. Wipf and W. S. Weiner, J. Org. Chem. 1999, 64, 5321-5324)with phenylacetylen (525 mg, 5.15 mmol), CuI (13 mg, 0.07 mmol) andPd(PPh₃)Cl₂ (24 mg, 0.04 mmol) in Et₃N/DMF (3:1).

[0236] MS ESI+: 267 (M−OH).

Example 47

[0237] Following general procedure F,[6,7-dimethoxy-2-(2-phenyl-[1,3]dioxolan-2-yl)-benzofuran-4-yl]-methanol(3.94 g, 98%) was obtained as an oil by6,7-dimethoxy-2-(2-phenyl-[1,3]dioxolan-2-yl)-benzofuran-4-carboxylicacid methyl ester (4.29 g, 11.16 mmol) with LiAlH₄ (980 mg, 24.5 mmol).

[0238] MS ESI+: 357 (M+H).

Example 48

[0239] Following general procedure G,2-biphenyl-4-ylmethyl-6,7-dimethoxy-benzofuran-4-carbaldehyde (105 mg,27%) was obtained as a solid by reacting(2-biphenyl-4-ylmethyl-6,7-dimethoxy-benzofuran-4-yl)-methanol (395 mg,1.06 mmol) with MnO₂ (1.73 g, 19.9 mmol)

[0240] MS ESI+: 373 (M+H).

Example 49

[0241] Following general procedure G,6,7-dimethoxy-2-(4-methoxy-benzyl)-benzofuran-4-carbaldehyde (20 mg,25%) was obtained as am oil by reacting(6,7-dimethoxy-2-(4-methoxy-benzyl)-benzofuran-4-yl]-methanol (79 mg,0.24 mmol) with MnO₂ (210 g, 2.42 mmol)

[0242] MS ESI+: 329 (M+H).

Example 50

[0243] Following general procedure G,2-(4-fluoro-benzyl)-6,7-dimethoxy-benzofuran-4-carbaldehyde (396 mg,56%) was obtained as an oil by reacting[2-(4-fluoro-benzyl)-6,7-dimethoxy-benzofuran-4-yl]-methanol (709 mg,2.24 mmol) with MnO₂ (1.948 g, 22.41 mmol)

[0244] MS ESI+: 315 (M+H).

Example 51

[0245] Following general procedure G,2-dimethylaminomethyl-6,7-dimethoxy-benzofuran-4-carbaldehyde (496 mg,77%) was obtained as a brawn oil by reacting(2-dimethylaminomethyl-6,7-dimethoxy-benzofuran-4-yl)-methanol (500 mg,1.88 mmol) with MnO₂ (1.64 g, 18.84 mmol)

[0246] MS ESI+: 264 (M+H).

Example 52

[0247] Following general procedure G,2-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-6,7-dimethoxy-benzofuran-4-carbaldehyde(638 mg, 71%) was obtained as a brown oil by reacting[2-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-6,7-dimethoxy-benzofuran-4-yl]-methanol(907 mg, 2.56 mmol) with MnO₂ (2.23 g, 25.66 mmol)

[0248] MS ESI+: 352 (M+H).

Example 53

[0249] Following general procedure G,6,7-Dimethoxy-2-morpholin-4-ylmethyl-benzofuran-4-carbaldehyde (489 mg,64%) was obtained as an orange oil by reacting(6,7-dimethoxy-2-morpholin-4-ylmethyl-benzofuran-4-yl)-methanol (765 mg,2.49 mmol) with MnO₂ (2.16 g, 24.89 mmol)

[0250] MS ESI+: 306 (M+H).

Example 54

[0251] Following general procedure G,2-[(4-fluoro-phenylamino)-methyl]-6,7-dimethoxy-benzofuran-4-carbaldehyde(197 mg, 28%) was obtained as an oil by reacting{2-[(4-fluoro-phenylamino)-methyl]-6,7-dimethoxy-benzofuran-4-yl}-methanol(718 mg, 2.16 mmol) with MnO₂ (1.88 g, 21.6 mmol)

[0252] MS ESI+: 330 (M+H).

Example 55

[0253] Following general procedure G,2-allyloxymethyl-6,7-dimethoxy-benzofuran-4-carbaldehyde (2.01 g, 72%)was obtained as an oil by reacting(2-allyloxymethyl-6,7-dimethoxy-benzofuran-4-yl)-methanol (2.82, 10.17mmol) with MnO₂ (8.80 g, 101.69 mmol)

[0254] MS ESI+: 277 (M+H).

Example 56

[0255] Following general procedure G,6,7-dimethoxy-2-(4-methoxy-benzyloxymethyl)-benzofuran-4-carbaldehyde(244 mg, 72%) was obtained as an oil solid by reacting[6,7-dimethoxy-2-(4-methoxy-benzyloxymethyl)-benzofuran-4-yl]-methanol(341 mg, 0.95 mmol) with MnO₂ (0.827 g, 9.51 mmol)

[0256] MS ESI+: 357 (M+H).

Example 57

[0257] Following general procedure G,6,7-dimethoxy-2-phenyl-benzofuran-4-carbaldehyde (121 mg, 81%) wasobtained as an oil by reacting(6,7-dimethoxy-2-phenyl-benzofuran-4-yl)-methanol (150 mg, 0.53 mmol)with MnO₂ (467 mg, 5.33 mmol)

[0258] MS ESI+: 283 (M+H).

Example 58

[0259] Following general procedure G,6,7-dimethoxy-2-(2-phenyl-[1,3]dioxolan-2-yl)-benzofuran-4-carbaldehyde(3.50 g, 97%) was obtained as a oil by reacting([6,7-dimethoxy-2-(2-phenyl-[1,3]dioxolan-2-yl)-benzofuran-4-yl]-methanol(3.65 mg, 10.24 mmol) with MnO₂ (9.8 g, 102 mmol)

[0260] MS ESI+: 355 (M+H).

Example 59

[0261] Following general procedure1,2-(2-biphenyl-4-ylmethyl-6,7-dimethoxy-benzofuran-4-ylmethyl-3-phenylamino-acrylonitrile(58 mg, 41%) was obtained after purification by flash chromatography 2:3ethyl acetate/hexane as a yellow oil from the reaction of2-biphenyl-4-ylmethyl-6,7-dimethoxy-benzofuran-4-carbaldehyde (1 05 mg,0.28 mmol) with 3-anilinopropionitrile (45 mg, 0.30 mmol) and potassiumtert-butoxide (36.4 mg, 0.32 mmol).

Example 60

[0262] Following general procedure1,2-[6,7-dimethoxy-2-(4-methoxy-benzoyl)-benzofuran-4-ylmethyl]-3-phenylamino-acrylonitrilewhich was used for the next step without further purification, wasobtained from the reaction6,7-dimethoxy-2-(4-methoxy-benzyl)-benzofuran-4-carbaldehyde(20 mg, 0.06mmol) with 3-anilinopropionitrile (9 mg, 0.06 mmol) and potassiumtert-butoxide (8 mg, 0.07 mmol).

Example 61

[0263] Following general procedure I,2-[2-(4-fluoro-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-3-phenylamino-acrylonitrilewhich was used for the next step without further purification, wasobtained from the reaction2-(4-fluoro-benzyl)-6,7-dimethoxy-benzofuran-4-carbaldehyde (395 mg,1.25 mmol) with 3-anilinopropionitrile (200 mg, 1.38 mmol) and potassiumtert-butoxide (170 mg, 1.50 mmol)

[0264] MS ESI−: 441 (M−H).

Example 62

[0265] Following general procedure I,2-(2-dimethylaminomethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-3-phenylamino-acrylonitrilewhich was used for the next step without further purification, wasobtained from the2-dimethylaminomethyl-6,7-dimethoxy-benzofuran-4-carbaldehyde (350 mg,1.33 mmol) with 3-anilinopropionitrile (223 mg, 1.53 mmol) and potassiumtert-butoxide (179 mg, 1.60 mmol)

[0266] MS ESI−: 390 (M−H).

Example 63

[0267] Following general procedure I,2-[2-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-3-phenylamino-acrylonitrile(414 mg, 52%) was obtained after purification by flash chromatography2:3 ethyl acetate/hexane as a yellow oil from the reaction of2-2-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-6,7-dimethoxy-benzofuran-4-carbaldehyde(584 mg, 1.66 mmol) with 3-anilinopropionitrile (279 mg, 1.91 mmol) andpotassium tert-butoxide (224 mg, 1.99 mmol)

[0268] MS ESI+: 480 (M+H).

Example 64

[0269] Following general procedure I,2-(6,7-dimethoxy-2-morpholin-4-ylmethyl-benzofuran-4-ylmethyl)-3-phenylamino-acrylonitrile(348 mg, 50%) was obtained after purification by flash chromatography2:3 ethyl acetate/hexane as a yellow oil from the reaction of6,7-dimethoxy-2-morpholin-4-ylmethyl-benzofuran-4-carbaldehyde (485 mg,1.59 mmol) with 3-anilinopropionitrile (267 mg, 1.82 mmol) and potassiumtert-butoxide (214 mg, 1.90 mmol)

[0270] MS ESI+: 434 (M+H).

Example 65

[0271] Following general procedure I,2-{2-[(4-fluoro-phenylamino)-methyl]-6,7-dimethoxy-benzofuran-4-ylmethyl}-3-phenylamino-acrylonitrilewhich was used for the next step without further purification, wasobtained from the2-[(4-fluoro-phenylamino)-methyl]-6,7-dimethoxy-benzofuran-4-carbaldehyde(197 mg, 0.60 mmol) with 3-anilinopropionitrile (100 mg, 0.69 mmol) andpotassium tert-butoxide (80 mg, 0.72 mmol).

Example 66

[0272] Following general procedure I,2-[6,7-dimethoxy-2-(4-methoxy-benzyloxymethyl)-benzofuran-4-ylmethyl]-3-phenylamino-acrylonitrile(123 mg, 38%) was obtained after purification by flash chromatography2:3 ethyl acetate/hexane as a yellow oil from the reaction of6,7-dimethoxy-2-(4-methoxy-benzyloxymethyl)-benzofuran-4-carbaldehyde(236 mg, 0.66 mmol) with 3-anilinopropionitrile (106 mg, 0.78 mmol) andpotassium tert-butoxide (85 mg, 0.761 mmol)

[0273] MS ESI−: 472 (M−H).

Example 67

[0274] Following general procedure I,2-(2-allyloxymethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-3-phenylamino-acrylonitrile(501 mg, 54%) was obtained after purification by flash chromatography2:3 ethyl acetate/hexane as a yellow oil from the reaction of2-allyloxymethyl-6,7-dimethoxy-benzofuran-4-carbaldehyde (626 mg, 2.26mmol) with 3-anilinopropionitrile (364 mg, 2.49 mmol) and potassiumtert-butoxide (292 mg, 2.60 mmol)

[0275] MS ESI−: 403 (M−H).

Example 68

[0276] Following general procedure I,2-(6,7-dimethoxy-2-phenyl-benzofuran-4-ylmethyl)-3-phenylamino-acrylonitrilewhich was used for the next step without further purification, wasobtained from the 6,7-dimethoxy-2-phenyl-benzofuran-4-carbaldehyde (120rng, 0.426 mmol) with 3-anilinopropionitrile (62 mg, 0.426 mmol) andpotassium tert-butoxide (48 mg, 0.426 mmol)

Example 69

[0277] Following general procedure I,3-[6,7-dimethoxy-2-(2-phenyl-[1,3]dioxolan-2-yl)-benzofuran-4-yl]-2-phenylaminomethyl-acrylonitrilewhich was used for the next step without further purification, wasobtained from the6,7-dimethoxy-2-(2-phenyl-[1,3]dioxolan-2-yl)-benzofuran-4-carbaldehyde(2.35 g, 6.63 mmol) with 3-anilinopropionitrile (1.02 g, 6.97 mmol) andpotassium tert-butoxide (0.86 g, 7.62 mmol)

[0278] MS ESI+: 483 (M+H).

Example 70

[0279]5-(2-Biphenyl-4-ylmethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamineformic acid salt (1 mg) was obtained as a white-yellow solid afterpurification by prep HPLC (RP C18, 10 mM Formic acid/ACN) by reactingguanidine hydrochloride (33 mg, 0.344 mmol), potassium tert-butoxide (41mg, 0.367 mmol) and2-(2-biphenyl-4-ylmethyl-6,7-dimethoxy-benzofuran-4-ylmethyl-3-phenylamino-acrylonitrile(57 mg, 0.115 mmol).

[0280] MS ESI+: 467 (M+H).

Example 71

[0281] Following General Procedure J.5-[6,7-dimethoxy-2-(4-methoxy-benzyl)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine(20 mg) was obtained as a yellow solid after crystallisation fromethanol by reacting guanidine hydrochloride (17 mg, 0.18 mmol),potassium tert-butoxide (20 mg, 0.18 mmol) and2-[6,7-dimethoxy-2-(4-methoxy-benzoyl)-benzofuran-4-ylmethyl]-3-phenylamino-acrylonitrile.

[0282] MS ESI+: 421 (M+H).

Example 72

[0283] Following General Procedure J,5-(2-(4-fluoro-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diaminehydrochloride salt (60 mg) was obtained as a dark yellow solid aftercrystallisation of the salt in ethrer/HCl by reacting guanidinehydrochloride (344 mg, 3.60 mmol), potassium tert-butoxide (404 mg, 3.60mmol) and2-[2-(4-fluoro-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-3-phenylamino-acrylonitrile.

[0284] MS ESI+: 409 (M+H).

Example 73

[0285] Following General Procedure J,5-(2-dimethylaminomethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(310 mg) was obtained as a yellow solid after crystallisation fromethanol by reacting guanidine hydrochloride (366 mg, 3.83 mmol),potassium tert-butoxide (430 mg, 3.83 mmol) and2-(2-dimethylaminomethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-3-phenylamino-acrylonitrile.

[0286] MS ESI+: 358 (M+H).

Example 74

[0287] Following General Procedure J,5-[2-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine(234 mg) was obtained as a yellow solid after crystallisation fromethanol by reacting guanidine hydrochloride (245 mg, 2.56 mmol),potassium tert-butoxide (288 mg, 2.56 mmol) and2-[2-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-3-phenylamino-acrylonitrile(410 mg, 0.85 mmol)

[0288] MS ESI+: 446 (M+H).

Example 75

[0289] Following General Procedure J,5-(6,7-dimethoxy-2-morpholin-4-ylmethyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(177 mg) was obtained as a yellow solid after crystallisation fromethanol by reacting guanidine hydrochloride (228 mg, 2.39 mmol),potassium tert-butoxide (268 mg, 2.39 mmol) and2-(6,7-dimethoxy-2-morpholin-4-ylmethyl-benzofuran-4-ylmethyl)-3-phenylamino-acrylonitrile(345 mg, 0.79 mmol).

[0290] MS ESI+: 400 (M+H).

Example 76

[0291] Following General Procedure J,5-{2-[(4-fluoro-phenylamino)-methyl]-6,7-dimethoxy-benzofuran-4-ylmethyl}-pyrimidine-2,4-diamine(4 mg) was obtained as a yellow solid after puritfication by TLCpreparative (SiO₂, CH₂Cl₂/MeOH, 9:1)) by reacting guanidinehydrochloride (163 mg, 1.05 mmol), potassium tert-butoxide (118 mg, 1.05mmol) and2-{2-[(4-fluoro-phenylamino)-methyl]-6,7-dimethoxy-benzofuran-4-ylmethyl}-3-phenylamino-acrylonitrile

[0292] MS ESI+: 424 (M+H).

Example 77

[0293] Following General Procedure J,5-[6,7-dimethoxy-2-(4-methoxy-benzyloxymethyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine(32 mg) was obtained as a yellow solid after crystallisation fromethanol by reacting guanidine hydrochloride (99 mg, 0.68 mmol),potassium tert-butoxide (76 mg, 0.68 mmol) and2-[6,7-dimethoxy-2-(4-methoxy-benzyloxymethyl)-benzofuran-4-ylmethyl]-3-phenylamino-acrylonitrile(110 mg, 0.23 mmol)

[0294] MS ESI+: 451 (M+H).

Example 78

[0295] Following General Procedure J,5-(2-allyloxymethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(299 mg) was obtained as a yellow solid after crystallisation fromethanol by reacting guanidine hydrochloride (531 mg, 3.63 mmol),potassium tert-butoxide (408 mg, 0.68 mmol) and2-(2-allyloxymethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-3-phenylamino-acrylonitrile(490 mg, 1.21 mmol)

[0296] MS ESI+: 371 (M+H).

Example 79

[0297] Following General Procedure J,5-(6,7-dimethoxy-2-phenyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(4 mg) was obtained as a yellow solid after crystallisation from ethanolby reacting guanidine hydrochloride (122 mg, 1.28 mmol), potassiumtert-butoxide (143 mg, 1.28 mmol) and2-(6,7-dimethoxy-2-phenyl-benzofuran-4-ylmethyl)-3-phenylamino-acrylonitrile.

[0298] MS ESI+: 377 (M+H).

Example 80

[0299] Following General Procedure J,5-(6,7-dimethoxy-2-(2-phenyl-[1,3]dioxolan-2-yl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine(440 mg) was obtained as a yellow solid after crystallisation fromethanol by reacting guanidine hydrochloride (890 mg, 9.3 mmol),potassium tert-butoxide (1.04 g, 9.3 mmol) and3-[6,7-dimethoxy-2-(2-phenyl-[1,3]dioxolan-2-yl)-benzofuran-4-yl]-2-phenylaminomethyl-acrylonitrile(1.5 gcrude).

[0300] MS ESI+: 449 (M+H).

Example 81

[0301][4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-yl]-phenyl-methanone;hydrochloride (107 mg, 25%) was obtained as a yellow solid aftercrystallisation from ethanol by reacting a solution of5-(6,7-dimethoxy-2-(2-phenyl-[1,3]dioxolan-2-yl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine(440 mg, 0.981 mmol) in ethanol with 6 N HCl for 16 h at r.t.

[0302] MS ESI+: 405 (M+H).

Example 82

[0303][4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-yl]-phenyl-methanol(10 mg) was obtained by reacting[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-yl]-phenyl-methanone(20 mg) with NaBH₄ Then the reaction was quenched with 1N HCl, theimpurities were extracted with ethyl acetate and the solutionneutralised with Na₂CO₃ to pH=7 and saturated with NaOAc. The compoundwas extracted with ACN dried over MgSO₄ and the solvent evaporated togive the desired compound.

[0304] MS ESI+: 407 (M+H).

Example 83 Deprotection of Hydroxyl

[0305] Under argon, to a solution of5-(2-allyloxymethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(610 mg, 1.64 mmol) in ACN was added Pd(PPh₃)₄ complex (571 mg, 0.424mmol) and ammonium formate (519 mg, 8.23 mmol). The reaction mixture wasstirred at reflux for 2 h. Then the reaction was quenched with 1N HCl,the impurities were extracted with ethyl acetate and the solutionneutralised with Na₂CO₃ to pH=7 and saturated with NaOAc. The compoundwas extracted with ACN dried over MgSO₄ and the solvent evaporated togive[4-(2,4-diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-yl]-methanol(497 mg, 84%) as a yellow solid.

General Procedure M Protection of the Keto Group

[0306] Under argon, to a solution of compounds VI (1 eq.) in dry toluenewas added ethylene glycol (6.5 eq.) and p-toluene sulfonic acid (0.15eq.). The reaction mixture was stirred at reflux for 16 h and the waterproduce during the reaction was distilled using a Dean-stark trap. Thereaction mixture was diluted with ether and the organic layer was washedwith H₂O, brine and dried over MgSO₄. Purification by FC hexane/ethylacetate (19:1) gave the expected compound X.

Example 84

[0307]6,7-Dimethoxy-2-(2-phenyl-[1,3]dioxolan-2-yl)-benzofuran-4-carboxylicacid methyl ester (5.08 g, 62%) was obtained as an oil by reacting2-benzoyl-6,7-dimethoxy-benzofuran-4-caboxylic acid methyl ester (7.22g, 21.21 mmol) with ethylene glycol (7.71 ml, 138.5 mmol) and pTsOH (609mg, 3.2 mmol)

General Procedure N Transformation to Chloro Derivatives

[0308] Under argon, to a solution of the alcohol (1 eq.) in ether orCHCl₃ was added thionyl chloride (1.5-1.7 eq.) and the reaction mixturewas stirred for lh at reflux. In the case of ether as solvent theorganic layer could be washed with H₂O, dried over MgSO₄ and the solventevaporated to give the chloride derivative VIII.2. In the case of CHCl₃as solvent, the solvent and the excess of thionyl chloride weredistilled under reduced pressure to give the chloride derivative XIX.

Example 85

[0309] 2-Chloromethyl-6,7-dimethoxy-benzofuran-4-carboxylic acid methylester (1.04 g, 97%) was obtained as a yellow solid by reacting2-hydroxymethyl-6,7-dimethoxy-benzofuran-4-carboxylic acid methyl ester(1.0 g, 3.75 mmol) with thionyl chloride (0.460 ml, 6.38 mmol) andpyridine (0.04 ml, cat.).

Example 86

[0310][4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-yl]-methanol(200 mg, 0.60 mmol) was reacted with thionyl chloride (0.066 ml, 0.90mmol) to give after direct evaporation of the solvent5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamineas a yellow oily compound which was used in the next step withoutfurther purification.

General Procedure O Friedel Craft's Alkylation

[0311] Under argon at 50° C., to a solution of the aromatic derivativesR⁵ (10 eq.) in CHCl₃ was added ZnCl₂ (1.2-2.4 eq.). A solution of thechloride derivative (1 eq.) in CHCl₃ was then slowly added within 30min. After stirring at 50° C. for 1-2 h the reaction was quenched withH₂O and the reaction mixture was partitioned between CH₂Cl₂ and NaHCO₃sat. The organic layer was separated, dried over MgSO₄ and the solventevaporated. The pure derivatives IX were obtained after purification byFC hexane/ethyl acetate (3:1). The pure derivatives I were obtainedafter dissolution the crude mixture in 1N HCl, extraction of thenonpolar impurities with ether, basification with Na₂CO₃ to pH=8 andextraction of the compound with ethyl acetate or CHCl₃. The organiclayer was then dried over MgSO₄ and the solvent evaporated to give thepure compound I.

Example 87

[0312]5-[2-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine(45 mg) was obtained as a dark yellow solid by reacting5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(155 mg, 0.454 mmol) with veratrol (0.529 ml, 4.45 mmol) and ZnCl₂ (68mg, 0.50 mmol)

[0313] MS ESI+: 451 (M+H).

Example 88

[0314]4-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-phenol(3 mg) was obtained after purification of a part of the reaction mixtureby TLC prep (SiO2) as a white-yellow solid by reacting5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(50 mg, 0.143 mmol) with phenol (135 mg, 1.43 mmol) and ZnCi₂ (23 mg,0.172 mmol).

[0315] MS ESI+: 407 (M+H).

Example 89

[0316]5-[6,7-Dimethoxy-2-(1-methyl-1H-pyrrol-2-ylmethyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine(3 mg) was as a yellow solid by reacting5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(50 mg, 0.143 mmol) with methylpyrrole (0.128 ml, 1.43 mmol) and ZnCl₂(47 mg, 0.34 mmol).

[0317] MS ESI+: 394 (M+H).

General Procedure P Coupling

[0318] Under argon, to a solution of pyrrol, indol, thiophenol or phenolHXR¹⁰ (1.5-2 eq.) in DMF was added NaH (1.5-2 eq.) and the mixture wasstirred for 1 h.5-(2-Chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(1 eq.) in DMF was then slowly added. The reaction mixture was stirredfor 18 h at r.t. After quenching the reaction with H₂O, the mixture waspartitioned between NaHCO₃ sat. and CHCl₃. The aqueous layer wasextracted several times with CHCl₃ dried over MgSO₄ and the solvent wasevaporated. The residue was dissolved in 1N HCl, extracted with ether,basified with Na₂CO₃ to pH=8 an extracted with CHCl₃. The CHCl₃ layerwas dried over MgSO₄, the solvent evaporated to give the pure compoundsI. The salts were obtained after treating the free base with thecorresponding acidic aqueous solution and freeze-drylng.

Example 90

[0319]5-[2-(4-Fluoro-phenoxymethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine;formic acid salt (48 mg, 76%) was obtained by reacting5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(52 mg, 0.151 mmol), NaH (9 mg, 0.226 mmol), and 4-fluororphenol (25 mg,0.226 mmol).

[0320] MS ESI+: 471 (M+H).

Example 91

[0321]5-[6,7-Dimethoxy-2-(4-trifluoromethyl-phenoxymethyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine;formic acid salt (33 mg, 47%) was obtained by reacting5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(52 mg, 0.151 mmol), NaH (9 mg, 0.226 mmol), and 4-trifluorophenol (337mg, 0.226 mmol).

[0322] MS ESI+: 521 (M+H).

Example 92

[0323]5-[2-(4-Fluoro-phenylsulfanylmethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine;formic acid salt (15 mg) was obtained by reacting5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(52 mg, 0.151 mmol), NaH (12 mg, 0.303 mmol), and 4-fluororthiophenol(0.032 ml, 0.303 mmol).

[0324] MS ESI+. 487 (M+H).

Example 93

[0325]N-{4-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethylsulfanyl]-phenyl}-acetamide;formic acid salt (20 mg) was obtained by reacting5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(52 mg, 0.151 mmol), NaH (12 mg, 0.303 mmol), and 4-acetaminothiophenol(56 mg, 0.303 mmol).

[0326] MS ESI+526 (M+H).

Example 94

[0327]4-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethoxy]-phenol(3 mg) was obtained after purification of a part of the reaction mixtureby TLC preparative (SiO₂) by reacting5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(75 mg, 0.215 mmol), NaH (13 mg, 0.322 mmol), and 4-hydroxyphenol (38mg, 0.344 mmol).

[0328] MS ESI+: 423 (M+H).

Example 95

[0329]5-[2-(4-Amino-phenoxymethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine(43 mg) was obtained by reacting5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(75 mg, 0.215 mmol), NaH (13 mg, 0.322 mmol), and 4-aminophenol (50 mg,0.344 mmol).

[0330] MS ESI+:422 (M+H).

Example 96

[0331]5-(6,7-Dimethoxy-2-pyrrol-1-ylmethyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(62 mg, 74%) was obtained by reacting5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(77 mg, 0.220 mmol), NaH (13 mg, 0.322 mmol), and pyrrole (0.022 ml,0.322 mmol).

[0332] MS ESI+: 380 (M+H).

Example 97

[0333]5-(2-lmidazol-1-ylmethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(24 mg, 28%) was obtained by reacting5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine(77 mg, 0.220 mmol), NaH (13 mg, 0.322 mmol), and imidazol (22 mg, 0.322mmol).

[0334] MS ESI+: 381 (M+H).

Example 98

[0335] Following procedure C,5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenol (Helv. Chim.Acta 1970, 53, 945) (200 mg, 0.687 mmol) was reacted with K₂CO₃ (71 mg,0.515 mmol) and ethyl-2-chloroacetoacetate (0.096 ml, 0.687 mmol) togive after work-up using CHCl₃ and NaHCO₃ sat solution andcrystallisation in ethanol,4-(2,4-diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-3-methyl-benzofuran-2-carboxylicacid ethyl ester as a yellow solid (150 mg, 57%)

[0336] MS ESI+: 387 (M+H).

Example 99

[0337]4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-3-methyl-benzofuran-2-carboxylicacid was (10 mg) obtained as a yellow solid after treating4-(2,4-diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-3-methyl-benzofuran-2-carboxylicacid ethyl ester with a 2N NaOH solution neutralisation of the solutionwith HCl and freeze-drylng.

[0338] MS ESI+: 359 (M+H).

Example 100

[0339] Following General Procedure G,4-(2,4-diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-carbaldehyde(10 mg) was obtained by reacting[4-(2,4-diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-yl]-methanol(15 mg, 0.04 mmol) and MnO₂ (4 mg, 0.4 mmol)

[0340] MS ESI+:329 (M+H).

Example 101 Biological Results

[0341] Antimicrobial susceptibility testing was performed in accordancewith the National Committee for Clinical Laboratory Standards (NCCLS)procedure [M7-A5, 2001]. M7-A5 (2001): Methods for DilutionAntimicrobial Susceptibility Tests for Bacteria That Grow Aerobically;Approved Standard—Fifth Edition American National Standard In vitroAntibacterial Activity of Compounds (Minimum Inhibitory Concentration(MIC) in micrograms/ml) End Product of Example Microorganism 20 21 72Trimethoprim Escherichia coil 4.0 2.0 2.0 0.25 ATCC 25922 Staphylococcusaureus 0.062 0.062 0.25 2 ATCC 25923 Streptococcus 0.125 0.50 0.5 2pneumoniae ATCC 49619 Staphylococcus 0.062 0.062 0.015 0.062 epidermidisATCC 12228 Enterococcus faecalis 0.500 0.125 1.0 0.5 ATCC 29212 Bacillussubtilis 0.062 0.062 0.25 0.5 ATCC 6051

1. Compounds of the general formula I

wherein R¹ represents straight or branched chain lower alkyl with 2 to 6carbon atoms; cycloalkylmethyl with 3 to 6 carbon atoms; aryl;arylmethyl or heteroarymethyl, the aryl and heteroaryl group may bemono-, di- or tri-substituted with halogen, amino, hydroxy, nitro,trifluoromethyl, lower alkyloxy, lower alkylcarbonylamino,arylcarbonylamino, whereby these substituents may be the same ordifferent; straight or branched chain lower alkylcarbonyl with up to 6carbon atoms; cycloalkylcarbonyl with 3 to 6 carbon atoms;cycloalkylhydroxymethyl with 3 to 6 carbon atoms; arylcarbonyl, the arylgroup may be mono-, di or tri-substituted with halogen, amino, loweralkyloxy, lower alkylcarbonylamino, arylcarbonylamino, whereby thesesubstituents may be the same or different; arylhydroxymethyl, the arylgroup may be mono-, di- or tri-substituted with halogen, amino, loweralkyloxy, lower alkylcarbonylamino, arylcarbonylamino, whereby thesesubstituents may be the same or different; straight or branched chainlower alkenyl with 2 to 6 carbon atoms; hydroxy-lower alkyl with 1 to 6carbon atoms; fluoro-lower alkyl with 1 to 6 carbon atoms; aryloxy-loweralkyl whereby the aryl group may be mono-, di- or tri-substituted withhalogen, amino, lower alkyloxy, lower alkylcarbonylamino,arylcarbonylamino, whereby these substituents may be the same ordifferent; arylthio-lower alkyl whereby the aryl group may be mono-, di-or tri-substituted with halogen, amino, lower alkyloxy, loweralkylcarbonylamino, arylcarbonylamino, whereby these substituents may bethe same or different; arylamino-lower alkyl whereby the aryl group maybe mono-, di- or tri-substituted with halogen, amino, lower alkyloxy,lower alkylcarbonylamino, arylcarbonylamino, whereby these substituentsmay be the same or different; lower alkenyloxy lower alkyl whereby thelower alkenyl group may contain 2 to 4 carbon atoms and the lower alkylgroup may contain 1 or 2 carbon atoms; benzyloxy lower alkyl whereby thebenzyl group may be mono-, di- or tri-substituted with halogen, amino,lower alkyloxy, lower alkylcarbonylamino, arylcarbonylamino, wherebythese substituents may be the same or different; lower alkylamino loweralkyl whereby the lower alkyl groups may contain 1 to 3 carbon atoms;heterocyclylmethyl containing one to three hetero atoms which can be thesame or different and which may be substituted with lower alkyl,halogen, amino, lower alkyloxy, hydroxy, lower alkylcarbonylamino,arylcarbonylamino and benzofused derivatives thereof. R² and R³independently represent hydrogen; lower alkyl with 1 to 3 carbon atoms;or together a lower alkylene group with 1 to 3 carbon atoms bridging theoxygen atoms and forming a five, six or seven membered ring; R⁴represents hydrogen; straight or branched chain lower alkyl with 1 to 4carbon atoms; and pharmaceutically acceptable salts and N-oxidesthereof.
 2. Compounds of formula I, wherein R¹ is straight or branchedchain lower alkyl with 2 to 6 carbon atoms; cycloalkylmethyl with 3 to 6carbon atoms; aryl; arylmethyl or heteroarymethyl, the aryl andheteroaryl group may be mono- or di substituted with halogen, amino,hydroxy, nitro, trifluoromethyl, lower alkyloxy, loweralkylcarbonylamino, arylcarbonylamino, whereby these substituents may bethe same or different, and R² and R³ are methyl or together are amethylen group bridging the oxygen atoms to which they are attached andR⁴ is hydrogen or methyl.
 3. Compounds of formula I, wherein R¹ is4-methoxy-benzyl, phenyl, benzyl, cyclopropylmethyl, 4-fluoro-benzyl,3,4-dihydro-1H-isoquinolin-2-ylmethyl, 4-methoxy-benzyloxymethyl,4-acetylaminophenyl-sulfanyl-methyl, 4-trifluoromethyl-phenoxymethyl,4-amino-phenoxymethyl, allyloxymethyl, phenyl-[1,3]dioxolan-2-yl,pyrrol-1-ylmethyl, 3,4-dimethoxy-benzyl, 4-hydroxyphenyloxymethyl,phenylcarbonylmethyl, 4-fluoro-phenoxymethyl, 2,2-dimethyl-propyl,4-fluoro-phenylsulfanylmethyl, hydroxymethyl, formyl,4-fluoro-phenylamino-methyl, imidazol-1-ylmethyl, dimethylaminomethyl,morpholin-4-ylmethyl, biphenyl-4-ylmethyl, ethoxycarbonyl, carboxy,4-hydroxybenzyl, furan-2-ylmethyl, thiophen-2-ylmethyl,thiophen-3-ylmethyl, 1-methyl-pyrrol-2-ylmethyl, pyridin-2-ylmethyl,pyridin-3-ylmethyl, pyridin-4-ylmethyl, 4-acetylaminobenzyl,4-amino-benzyl, 4-nitro-benzyl, 4-acetylamino-3-methoxy-benzyl,4-amino-3-methoxy-benzyl, 3-acetylamino-4-methoxy-benzyl,3-amino-4-methoxy-benzyl, allyl, isopropenyl or halogenmethyl, and R²and R³ are methyl or together are a methylen group bridging the oxygenatoms to which they are attached and R⁴ is hydrogen or methyl. 4.Compounds of formula I, wherein R¹ is 4-methoxy-benzyl, phenyl, benzyl,cyclopropylmethyl, 4-fluoro-benzyl,3,4-dihydro-1H-isoquinolin-2-ylmethyl, 4-methoxy-benzyloxymethyl,4-acetylaminophenyl-sulfanyl-methyl, 4-trifluoromethyl-phenoxymethyl,4-amino-phenoxymethyl, allyloxymethyl, 3,4-dimethoxy-benzyl,4-hydroxybenzyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl,pyridin-4-ylmethyl, 4-acetylaminobenzyl, 4-amino-benzyl,4-acetylamino-3-methoxy-benzyl, 4-amino-3-methoxy-benzyl,3-acetylamino-4-methoxy-benzyl, 3-amino-4-methoxy-benzyl or aryl methyland R²and R³ are both methyl and R⁴ is hydrogen.
 5. Compounds of formulaI, wherein R¹ is 4-methoxy-benzyl, benzyl, cyclopropylmethyl,4-fluoro-benzyl, 3,4-dihydro-1H-isoquinolin-2-ylmethyl,4-amino-phenoxymethyl, 4-hydroxybenzyl, pyridin-2-ylmethyl,pyridin-3-ylmethyl, pyridin-4-ylmethyl, 4-acetylaminobenzyl,4-amino-benzyl, 4-acetylamino-3-methoxy-benzyl,4-amino-3-methoxy-benzyl, 3-acetylamino-4-methoxy-benzyl,3-amino-4-methoxy-benzyl and R² and R³ are both methyl and R⁴ ishydrogen
 6. The compounds according to any one of claims 1 to 55-[6,7-Dimethoxy-2-(4-methoxy-benzyl)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-(6,7-Dimethoxy-2-phenyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,5-(2-Benzyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,5-(2-Cyclopropylmethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,5-[2-(4-Fluoro-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,5-[2-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(4-methoxy-benzyloxymethyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,N-{4-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethylsulfanyl]-phenyl}-acetamide,5-[6,7-Dimethoxy-2-(4-trifluoromethyl-phenoxymethyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,5-[2-(4-Amino-phenoxymethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,5-(2-Allyloxymethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(2-phenyl-[1,3]dioxolan-2-yl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,5-(6,7-Dimethoxy-2-pyrrol-1-ylmethyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,5-[2-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,4-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethoxy]-phenol,[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-yl]-phenyl-methanone,5-[2-(4-Fluoro-phenoxymethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,5-[2-(2,2-Dimethyl-propyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[2-(4-Fluoro-phenylsulfanylmethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-yl]-methanol,4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-carbaidehyde5-{2-[(4-Fluoro-phenylamino)-methyl]-6,7-dimethoxy-benzofuran-4-ylmethyl}-pyrimidine-2,4-diamine,5-(2-lmidazol-1-ylmethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,5-(2-Dimethylaminomethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,5-(6,7-Dimethoxy-2-morpholin-4-ylmethyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,5-(2-Biphenyl-4-ylmethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-3-methyl-benzofuran-2-carboxylicacid,4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-3-methyl-benzofuran-2-carboxylicacid ethyl ester,5-[6,7-Dimethoxy-2-((4-chlorobenzyl)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(1-naphthylmethyl)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(2-propenyl)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-(6,7-Dimethoxy-2-trifuoromethylbenzofuran-4-ylmethyl)pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(2,2-dimethylpropan1-one)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(cyclopropylcarbonyl)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(4-methoxyphenyl-methanone)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(4-chlorophenyl-methanoneI)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(4-fluorophenyl-methanone)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(1-naphthylmethanone)-benzofuran-4-ylmethyljpyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(2,2-dimethyl-1-hydroxypropyl)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(cyclopropylmethanol)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(phenylmethanol)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-((4-methoxyphenylmethanol)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-((4-chlorophenyl)methanol)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-((4-fluorophenylmethanol)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dirfhethoxy-2-(1-naphthylmethanol)-benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[2-(3,4-Dihydro-2H-quinolin-1-ylmethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(tetrazol-5-ylmethyl)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(indol-1-ylmethyl)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(imidazol-1-ylcarbonyl)benzofuran-4-ylmethyl]pyrimidine-2,4-diamine,5-(2-Furan-2-ylmethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-0,4-diamine,5-(6,7-Dimethoxy-2-thioph en -2-ylmethyl-benzofuran -4-ylmethyl)-pyrimidine-2,4-diamine,5-[6,7-Dimethoxy-2-(1-methyl-1H-pyrrol-2-ylmethyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,5-(6,7-Dimethoxy-2-pyridin-2-ylmethyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,5-(6,7-Dimethoxy-2-pyridin-3-ylmethyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,5-(6,7-Dimethoxy-2-pyridin-4-ylmethyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,4-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-phenol,N-{4-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-phenyl}-acetamide,5-[2-(4-Amino-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,5-(6,7-Dimethoxy-2-(4-nitro-benzyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,N-{4-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-2-methoxy-phenyl}-acetamide,5-[2-(4-Amino-3-methoxy-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,N-{5-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-2-methoxy-phenyl}-acetamide,5-[2-(3-Amino-4-methoxy-benzyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine,5-(6,7-Dimethoxy-2-thiophen-3-ylmethyl-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine,and pharmaceutically acceptable salts and N-oxides thereof. 7.Pharmaceutical compositions for the treatment of infections containing acompound of any one of claims 1 to 6 and usual carrier materials andadjuvants.
 8. Pharmaceutical compositions for the treatment ofinfections caused by Gram positive and Gram negative pathogens,containing a compound of any one of claims 1 to 6 and usual carriermaterials and adjuvants.
 9. The compounds of any one of the claims 1 to6 for use as medicaments for the treatment of infections.
 10. Thecompounds of any one of the claims 1 to 6 for use as medicaments for thetreatment of infections caused by Gram positive and Gram negativepathogens.
 11. The use of one or more compounds of any one of claims 1to 6 as active ingredients for the production of pharmaceuticalcompositions for the treatment of infections.
 12. The use of one or morecompounds of any one of claims 1 to 6 as active ingredients for theproduction of pharmaceutical compositions for the treatement ofinfections caused by Gram positive and Gram negative pathogens.
 13. Aprocess for the manufacture of pharmaceutical compositions for thetreatment of infections containing one or more compounds as claimed inany one of claims 1 to 6 as active ingredients which process comprisesmixing one or more active ingredient with pharmaceutically acceptableexcipients in a manner known per se.
 14. A process for the manufactureof pharmaceutical compositions for the treatment of infections caused byGram positive and Gram negative pathogens containing one or morecompounds as claimed in any one of claims 1 to 6 as active ingredientswhich process comprises mixing one or more active ingredient withpharmaceutically acceptable excipients in a manner known per se.
 15. Theinvention as hereinbefore described.